PKinetics Multicomptt

CHAPTER 11 Multicompartment Modeling
Author: Michael Makoid

Reviewer: Phillip Vuchetich
OBJECTIVES
1. This chapter is not completed.
Basic Pharmacokinetics REV. 99.4.25 11-1

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Multicompartment Modeling
11.1 Executive Summary

11.2 Equations

11.3 PHARMCOKINETICS: MAMMILLARY MODELS
For many drugs the equilibrium between drug concentrations in different tissues is
not achieved rapidly. Thus, one of the assumptions of the one-compartment open
model sometimes becomes invalid. A more complex mammillary open model is
often necessary to describe mathematically the plasma concentration data (for
example) seen after the administration of some drugs. The simplest mammillary
open model is a two-compartment open model: for example:
Compartment One (central compartment) can be sampled through the blood (or
plasma, or serum). It may consist of organs or tissues which, being highly perfused
with blood, are in rapid equilibrium distribution with the blood.
Compartnent Two (peripheral compartment) cannot normally be sampled. It may

consist or organs or tissues which, being poorly perfused with blood, are in slow
equilibrium distribution with the blood.
The Body is the sum of both compartments.

1. Biexponential Properties of Two-Compartment Open Model
Following an intravenous bolus injection, the plasma concentration against time

profile has two phases:
a. Initial phase - ( α - phase)
b. Terminal phase - ( β - phase)
On semilogarithmic paper the terminal phase is linear, indicating that initial distri-
bution has been completed and that equilibrium has been attained. The terminal
half-life ( t 1 ⁄ 2 ) can be measured from the terminal phase.
2. Intravenous Bolus Administration: Plasma Concentration Data
For a one-compartment open model,
– kt
Cp = ( Cp )o e (EQ 10-26)
i.e., the concentration of drug in the plasma declines exponentially with time
For a two-compartment open model,

– αt – βt
Cp = ( A1 e + B1 e ) (EQ 10-27)
i.e., the concentration of drug in the plasma declines biexponentially with time
2.1 Symbols
3
A 1 and B1 are intercept constants ( M ⁄ L )
–1
α and β are hybrid rate constants ( T )
V 1 is the apparent volume of unchanged drug distribution in compartment one

3
(L )
–1
k 10, k 12 , and , k 21 are “micro” rate constants ( T )
2.2 Relationships (for reference, except Eq. 3)
2
α = 0.5 [ ( k 10 + k 12 + k 21 ) + ( k 10 + k 12 + k 21 ) – 4k 10k 12 ]

2
β = 0.5 [ ( k 10 + k 12 + k 21 ) – ( k 10 + k 12 + k 21 ) – 4k 10k 12 ]
D- ( α – k 21 )
A 1 = ----- • ----------------------
V1 ( α – β )
( k 21 – β )
D- • ---------------------
B 1 = -----
V1 ( α – β )
A 1 + B1 = ( Cp ) o (EQ 10-28)
2.3 Obtaining Pharmacokinetic Parameters by “Feathering”
By convention, α > β
a. Plot C p against t on semilogarithmic paper
b. Find t 1 ⁄ 2 from the linear terminal phase: see “Intravenous Administration”,

section A1.4a
c. Calculate the terminal hybrid rate constant ( β ) ; in reality it contains both dis-
tributive ( k 12 and k 21 ) and elimination ( k 10 ) factors.
0.693
β = ------------- (EQ 10-29)
t1 ⁄ 2

d. Draw a straight line through the linear terminal elimination phase and extralpo-
late this line to t = 0. The intercept is equal to B1 .
e. Read estrapolated plasma concentrations ( C p ) from the plot at times equal to

those given for values of C p which are prior to the terminal phase.
f. At each of these times calculate:
( C p )diff = C p – C p
g. Plot ( C p )diff against t (see Eq.8) on semilogarithmic paper. The is a “feath-

ered” line and should decline linearly.
h. Find the half-life of the plot. It wil refer to the initial phase. Calculate,
0.693 -
α = ------------------------
half – life
i. Measure the intercept of the “feathered” line; it will equal to A 1 (Note that usu-
ally A1 = B1 , even theoetically).

j. Calculate ( C p )o from Eq. 3
k. Calcultate V1 by
Xo D
V1 = ------------- = ------------------ (EQ 10-30)
( Cp )o A1 + B 1
Theory
– αt – βt
When t is large, e <e . Hence, Eq. 2 becomes
– βt
Cp = B1 e (EQ 10-31)
i.e., when t is large, the concentration of the drug in the plasma declines exponen-
tilly with time.
The extrapolated plasma concentrations are

– βt
Cp = B1 e (EQ 10-32)
Substituting from Eqs. 2 and 7a into Eq. 5,

– βt
( C p ) diff = A 1 e (EQ 10-33)
i.e., the difference between observed and extrapolated drug concentrations in the
plasma declines exponentially with time.
Note (for reference only)
It is usually not informative to determine the “micro”rate constant; but see one use
under the note on dosage regimens.
αB 1 + βA1
k 21 = -------------------------
-
A 1 + B1
k 10 = αβ ⁄ k 21
k 12 = α + β – k 10 – k 21
2.4 Clearance and Volume
If model-independant equations can be used to define these terms, this is preferred.
a. Systemic Clearance (Cl) may be calculated by,

D -
Cl = ---------------------- (EQ 10-34)
∞
( AUC )o
b. The volume terms are complex than in a one-compartment open model. There
are two terms of interest:
The apparent volume of distribution in compartment one ( V1 )
This is calculated using Eq. 6.
The apparent volume of distribution at pseudo-distribution equilibrium ( V β )
This volume may be defined only in relation to the terminal phase ( β phase), when
initial distribution has been completed.
D
V β = --------------------------
-
∞
β ( AUC )o
As Vβ requires calculation of the total area under the plasma concentration against
time curve it is sometimes known as Varea .
c. Comparing Eqs. 9 and 10,
Cl = βV β (EQ 10-35)

It may also be shown that,
Cl = k 10V 1 (EQ 10-36)
This follows as systemic clearance is always given by the elimination rate constant
out of the body multiplied by the apparent volume of distribution in the compart-
ment from which drug leaves the body. Comparing Eqs. 11 and 12,
k 10
V β = ------
-V (EQ 10-37)
β 1
Note that k 10 (the elimination rate constant) is not the same as β (the terminal
hybrid rate constant).
2.5 Bioavailability
∞
Find ( AUC )0 using trapezoidal rule and, if necessary, the calculation for the ter-
minal area.
∞ t C
( AUC )o = ( AUC )o + -----p- (EQ 10-38)
β
This is a model-independent equation.

2.6 Dosage Regimens
The maintenance dose (D) is given by the same model-independent equation as

before,
D = ( C p ) ss Cl • τ
Where ( C p )ss has its same previous definition.
The loading dose ( D L ) achieves a steady-state condition quite rapidly, but only
after initial distribution has been completed. It is given by the previous equation.
D
D L = --------------------------- (EQ 10-39)
– 0.693N
1–e
As may be expected, equations relating ( C max )ss and ( C min ) ss to ( C p )ss are as
before,
Note (reference only)
All dosage regimen equations strictly apply only when,

β-  1 + k------
12 
------  - = 1
k 10  k 21 
For digoxin Eq. 17 has a value of 0.947
For warfarin Eq. 17 has a value of 0.990
For cephalexin Eq. 17 has a value of 0.846
This is why, despite the fact that an open two-compartment model is better descrip-
tion of the pharmacokinetic of these drugs, a simple open-compartment model may
often be assumed for dosage regimen purposes.
3. Intravenous Bolus Administration: Compartment Two
It is not normally possible to measure drug concentrations in compartment two.

However, the mass of drug can be predicted based on the ddrug concentrations
observed in compartment one.
2.6 Dosage Regimens
– βt – αt
X2 = B2 ( e –e ) (EQ 10-40)
k 12D
Where B2 = -----------------
(α – β)

Note that the equations forms bears a similarity to that seen for plasma concentra-
tions after oral administration inot a one compartment open model.
– αt – βt
When t is large, e <e . Hence, Eq. 18 becomes,
– βt
X2= B2 e (EQ 10-41)
This is comparted to the mass modification of Eq. 7,

– βt
X1= V1B1 e (EQ 10-42)
Thus, when t is large the masses of drug in each compartment decline exponen-
tially, and in parallel, with time. This indicates that initial distribution has been
completed and equilibrium attained.
If the value of X 2 reflects drug concentrations at the active site, the time of maxi-
mum concentration (and maximum pharmacological effect) is:
ln ( α ⁄ β )
t max = --------------------- (EQ 10-43)
α–β
4. Others Dosage Forms
The equations become complex and it is therefore difficult to obtain useful param-
eter values without th eaid of a computer. Fortunately, because the complexity of
the equations is greater than the experimental accuracy of the assays warrants,
drugs that strictly require a mammillary model can be described adequately by an
open one compartment for the purposes of calculating dosage regimens.
4.1 Intravenous Infusion
The plasma concentrations at first rise faster than an open one compartment model
profile would suggest. Later, the rise is slower. The decline, following the cessa-
tion of infusion, is biexponential.
4.2 Oral Administration

At a time just after t max the plasma concentration may exhibit a “nose”, when
compared to the profile of an open one-compartment model.
SELECTED REFERENCES
Riegelman, S., Loo, J.C.K., and Rowland, M., Shortcomings in pharmacokinetic

analysis by conceiving the body to exhibit properties of a single campartment, J.
Pharm . Sci., 57, 117-123 (1968).
Riegelmen, S., Loo, J.C.k., and Rowland, M., Concept of a volume of distribution
and possible errors in evaluation of this parameter, J. Pharm. Sci., 57, 128-133
(l968).
Benet, L.Z. and Ronfeld, R.A., Volume terms in pharnacokinetics, J. Pharm. Sci.,
58, 639-641 (l969).
Gibaldi, M Nagashima, R., ant Levy, G., Relationship between drug concentra-
tions in plasma or serum and amount of drug in the body, J. Pharm. Sci., 58, 193-
197 (1969).
Metzler, C.M Usefulness of the two-compartent open model in pharmacokinetics,

J. Amer. Stat. Assn., 66, 49-54 (1971).

Gibaldi, M. and Perrier, D., Drug eliminatin and apparent volume of distribution in
multicompartment systems, J. Pharm. Sci., 61, 952-954 (1972).
Gillette, J.R., The importance of tissue distribution in pharmacokinetics, J. Phar-

macokinetics. Biopharm., 1, 497-520 (1973).
DRUG DISPOSITION: VOLUME TERMS
As apparent volumes of distribution are proportionality constants, and not physio-

logical volumes, more than one term is of value.
1. Apparent Volume of Sampled Compartment ( V1 )
This relates the concentration of drug in the sampled compartment with the mass
of drug present in that compartment.
It may be measured after an intravenous bolus dose:
D
V 1 = ------------- (EQ 10-44)
( Cp )o
D
or V1 = --------------------------- (EQ 10-45)
∞
K ( AUC )o
It may be measured after an intravenous infusion by:
( X1 ) ss Q
V 1 = --------------
- = ------------------- (EQ 10-46)
( C p ) ss K ( C p ) ss

2. Apparent Volume at Pseudo-Distribution Equilibrium ( Vβ )
This volume term (sometimes known as the apparent volume of distribution of the
drug in the body) requires the assumption that the drug is evenly distributed
throughout the body. The assumption is not true in practice. Thus Vβ can only be
defined in relation to the terminal phase ( β -phase) when equilibrium has been
attained; the equation is analogous to Eq. 2.
D
Vβ = --------------------------
- (EQ 10-47)
∞
β ( AUC )o
3. Relationships Between Apparent Volumes
By secondary alebraic definition, a clearance (Cl) is always given by the first-order

rate constant for removal of drug from the body multiplied by the apparent volume
of distribution on the drug in the compartment from which the drug leaves the
body:
Cl r = k u V 1 (EQ 10-48)
Cl m = k m V1 (EQ 10-49)
Cl s = KV 1 (EQ 10-50)
However, systemic clearance is measured by
D -
Cl s = ---------------------- (EQ 10-51)
∞
( AUC ) o
Comparing Eqs. 4 and 8, and rearranging,

Cl s = βVβ (EQ 10-52)
Comparing Eqs. 7 and 9,
K
V β = ---
-V (EQ 10-53)
β 1
Selected References
Riegelman, S., Loo, J.C.K., and Rowland, M., Concept of a volume of distribution
and possible errors in evaluation of this parameter, J. Pharm. Sci., 57, 128-133
(1968).
Benet, L.Z. and Ronfeld, R.A., Volume terms in pharmacokinetics, J. Pharm. Sci.,
58, 639-641 (1969).
Gibaldi, M., Nagashima, R., and Levy, G., Relationship between drug concentra-
tions in plasma or serum and amount of drug in the body, J. Pharm. Sci., 58, 193-
197 (1969).
Perrier, D. and Gibaldi, M., Relationship between plasma or serum drug concentra-
tion and amount of drug in the body at steady state upon multiple dosing, J. Phar-
macokin. Biopharm., 1, 17-22 (1973).
Oie, S. and Tozer, T.N., Effect of altered plasma protein binding on apparent vol-
ume of distribution, J. Pharm. Sci., 68, 1203-1205 (19793).
Li;vxrX LLrLLxLS

Drug is usuallo sampled from the centr->l compartment, designated compartment

one.
1. Laplace Transforn for Compartment One
As,l
(in)(dS 1)
where As,l is Laplace Transform for mass of drug in comPartment one
s is the Laplace Operator in is the input function
dS,l is ehe disposition function for compartment one
2 InDut Functions
. .
N ehat input need not necessarily be to compartment one.

2.1 IV Bolus
(in) - D
where D is the dose
2.2 IV Infusion
Q (l-e sb)
where Q is the zero-order infusion rate, b-t when e<T, b-T when eiT, and T is the
eime of cessation of infusion.
2-3 First-order Absorption
(in) . <
(s+ka)
where ka is first-order absorption rate constant, ant F is the fraction of D ultimately

reaching the general circulation.
2-4 Dissolution and Absorpcion (type 1)
(in) - krkaFD

(s+kr) (s+ka)
where kr is tirst-order dissolution rate constant.
2 5 Dissolution and Absorption (tvpe 2)
(la)
ka(l-e sb)
s(s+k>)
where ko is zero-order dissolution rate, ceasing at time T.
2-6 Others
These may be formed by adtition of functions 2-1 through 2-5
e.g., (in) - D + Q(l-e~Sb)
This denotes the simultaneous commencement of an I.V. bolus and infusion.

3. Disposition Function for Comcartment One
A driving force compartment has one or more exit rate constanes; for
instance, in compartment i, ehe sum of ehe first-order exit rate constants
is Ei.
As,~
n~
kca ‘a +
where q is the compartment into which input occurs, n is the number of driving
force compartments,
i,j, and m are counters (maximum value of n),
kql is the first-order rate constant for transfer of drug from input compartment eo
compartment one,

kl; and kjl are the first-order rate constants for drug transfer from compartment 1 to
compartment j, ant vice-versa.
3-1 Using the disposition function
(a) If q-l, ehen kqlsl
(b) Tr (Pi) and fT (Pm) are coneinued produces. ~e value of Pi (or Pm) equals one
when thc counter i (or m) takes on a forbidden number. For example, i-l is forbid-
den in the numerator, ant m-l and m-j are forbidden in the denominaeor. 3-Z
E.camples
(a) one-compartmene open model (n-l,q=l)
ds,l = 1 (Eq.l)
(b) Two-compart:.ent open models (n-2.q=1)
(s+E~)
ds , 1
(s+El) (s+E2) - kl2kx
(c) Three-compartmene open models(n-3,q-2)

dS,l
k21 (s+E3)
(Eq.2)
(s+El) (s+E2) (s+E3) - kl2k21 (s+E3) - kl3t31 (5tk2)
(Eq.3)
3-3 Simplifying the Denominator The number of exponeneial terms in ehe final
ineegrated equation will be equal eo the number of driving force compartments
(n). This is also equal to the maximum power to which the Laplace operator (s)
would nppear if
the denominator were multiplied out. Hence, the denominator is simplified n to

become iXl (S+ki), where ki is a composite first-order rate constane.
(a) ds,l ‘
(b) d5 l
(c) ts.l

(s+kl)
(s+E2)
(s+kl) ts I k2)
k21 (s+E3)
( s+kl ) ( s+k2 ) ( s+k3 )
(Eq.la)
(Eq.2a)
(Eq.3a)
The exact meaning of [i for any model depends on the equalities evident in the
denominaeors. Example for (b):
(s+kl) (s+k2) - (s+El) (s+E2) - kl2k

4. Method of Partial Fractions Ihis method is used to solve (integrate) a Laplace

Iransform providing there are no repeating factors in the denominator. Example:
no 52 or (s+ki)2
‘l 1 Prepare che Laplace Transform
Example: I.V. bolus into compartment one of two compartment model
( s+kl ) ( S+k2 )
4-2 Obtaining the Roots of Denominator Factors
If the factor is s, the rooc is zero
If ehe faceor is (s+ki), the root is
4-3 “Ridden-Hand” Method
(a) Deal with each factor of ehe tenominator in turn.
(b) Cover the factor with a finger, and remember its root.

(c) Wherever the Laplace operator(s) occurs in the uncovered transform, subseitute
the root for s.
(d) Multiply the resule by eses again substituting ehe rooe for s
(e) After doing (b) through (d) for each factor, simplify.
Example:
X1 ‘ D(-kl+E2)e-klt - + D(-k2+E2)e~k2t
(-kl+k2)(-k7+kl )
or C1 - D (kl-Ez)e kl + D (E2-k2)e 2
V1 (kl k2 )
or C1 - Ale 1 + A2e-k2t
In this example the meaning of A1, A2, kl, k2, and E2 depend on the form
of the two-compartmental model.

5. Laplace Transform for Peripheral Compartments
This is obtained by the following procedure, which is analogous eo that
employed when using the Laplace Transform table.
(a) Write the differential rate equation.
(b) Take the Laplace Transform of each side of the differential rate equation, using
the table where necessary.
V1 (kl-k2)
(c) Algebraically manipulate the transformed equation until an equation having

onlv one transformed dependent variable on the left-hand side is obtained.
(t) Substitute for anv known transformed dependent variables on tlle right-lland
sidc of the equation.
(e) Solve (integrate) bv the method of partial fractions (tlle “hidden 1land”), and
simplifv.

6. btethod if Denominator Contains the Factor 52 This may apply to terminal

“compartments”, such as urine, following an I.V. infusion. The “hidden hand”
method cannot be used for the factor 52 in the denominator as it has no simple
root.
6-1 Example (n=2, q^l, exit from compartmenr one):
aS,U - kloQ.(l-e~sb)(s+Es)
52(5+kl) (s+k2)
where klo is the first-order excretion rate constant from compartment one.
xu ~ kloQ.E2b + ......
klk2
where Xu is the cumulative mass of drug excreted into the urine.
The other factors can be used as before in the “hidden-hand” method.
6-2 Example (n-3, q-l, exit from compartment one)
aS u ‘ kloQ.(l-e 5b)(S+E2)ts+E3)
s2(s+kl)(s+kv)(s+k3)
Xu t kloQ- E2Elb I

klk2k3
REFERENCES
L.Z. Benet, General treatment of linear mammillary models with elimination from
any compartment as used in pharmacokinetics, J. Pharm. Sci., 61, 536-541 (1972)
D.P. Vaughan, D.J.H. Mallard, A. Trainor, and M. Mitchard, General pharmacoki-

netic equations for linear mammillary models with trug absorption into peripheral
compartments, Europ. J. Clin. Pharmacol., 8, 141-148 (1975).
D.P. Vaughan and A. Trainor, Derivation of general equations for linear mammill-
ary models when ehe drug is administered by different routes, J. Pharmacokin.
Biopharm., 3, 203-218 (1975).
Two-Compartment Model-l
Prior inputs focuset on one-compartmcnt models, but many drugs arc charactetizet
bettcr by multicompartmcnt motek. In the following three inputs, we shall bricfly
tiscuss multico~_nt motek ant prcstnt a few apB plicadons. Multicompartnent mot-
cis are not uset as fo quentlg u the one-compartment model in therapeutic trug
monitonng, panly because they arc more tifficult to construct ant apply.
Gencially, muldeaw models arc appliet when th,e natural log of plasma drug con-
sentration vcrsus time is not lincar afier an intravenous tose or when thc plasma
concentration versus time psfilc cannot bc chu~ by a single cxpooential function
(i.c., C, - CO e~~’). Wben the In of plasma concentration vcrsus timc is not a

stnight line, a multicompartmcnt model must bc constructet to tescribe the change

in concentrations over time.
Of the mul
models, tbe two-compartment motel is tnost fxqucntly uset. lunis model usually
of thc weU-perfia
tissues ant • “penpbexal” compartment of less weU Erfuset dssues (such as muscle
ant fat). hgure 23^ shows a diagram of thc two-compartmcnt model afir an intrave-
nous bolus tose, where:
consists of a “central’
Xf—amount of diug in centnl comva XP s amount of drug in psipheral cowt
K,2—rate const nt for transfcr of drug from cd-compartment zo petipheral com-

partment rne subsaipt “12” irldicses tr nsfcr from thc first (cd) to the second
(peripheral) compattments.
K2, - rate constant for tgansfcr of drugfrov peripheral computment to central comp
rtment lbe subscript ‘’21” indicales tr nsfcr from Ulc second (periphaal) to the fint
Xo~

Kl2
K2l
+ Klo
•zgre23~ Gr phic reprtsentation of a zwbcompattment model.
(centri) compartments. (Nott h Kz2 and K2,—calkd micxnts.)
fintvder climinX aue consunt (similar to tbe Jr uxd paviously), i—”ting elimiXn of
dmg out of tbe caul ~ into urine, feces,
esc~
A log plasma conscatration versus time curve for a two-compattment model shows
a curvilinear profile—a atrved potoon followed by a straight li=. This “biexponen-
tial” curve c n bc described by two expoKntial tcrms (Flgure 23B). lEc phases of
the curve may reprcstnt rapid d1stributioo to organs with high blood flow (central
compuenent) and slower distnbution to organs with Ess blood flow (penphcnl
compartmcnt).
Mer thc intovenous injection of a drug that follows a t_ model, thc drug consentra-
tions in all fluids and dmms associated with tbc central compartmcnt declinc morc
rapidly in tbc distributioo phasc thao during the post-diwibubon phasc. ARcr sornc

tirnc, a “pseudocquihEutn” is attained betwcen thc ccotral compartmcot and thc

dssucs atid fluids of toc pc ipheral compO thc pl sma coocentration vcrsus timc
ptnfile is thco chaserized by a linear pnmcess.
For many drugs, suco as aminoglycosides, thc distributdoo phast is vcry shott (e.g.,
1920 mtn). If serum consentradons are measured after this phase is compited, toe
ceotral compartmcot can be ignorcd and a one-compartrKnt model adequatcly
repttsents the serum coocentratioos observed. However, for drugs such as vanco-
mycin, thc-distribution phase lasts 1-2 hr after an intravenous dosc. If plasma con-
centrations of vancomycin are determined within the first hour after a dose is
given, thc nonlincar (multiexponential) decline of vancomycin concentrations
must bc considered.
REVIEW PROBLEMS
23.1. In the twocompartment model. Xt wpresents the
23.2. The log plasms concentration vcrsus time curve for a two-compartment
model is reprcsented by a (bicxponential or monoexponential) cuNe. (Sclect one.)
23.3. The first portion of the log plasma concentration ver. sus timc cune. where
the log concentration r;tpidly declincs. is lomwn as the
phasc.
23.4. The final. Iinear portion of the curve is the phase.

11- 1
~1
I>Pur 2t 61
70 [ So
~i
~m
~.
F*wf 238 Four st ges of drug distribution nd eliminatioo following rapid intrave-
nous injectiott. Points I, U, m, nd tv (ript) corrcspond to the points oo the plasmx
concentntion curve (leR). Point 1: The injection has just becn compicted, and drug
density io the cd compartment is hipcst. Drug distribution and elimination hve just
begun. Poin~ 11: At midway through tbe distributioo process, the drug density in
thc central compartment is falling r pidly, dulioly owing to rapid drug distributioo
out of the centd ccrnpartment into the peripheral compartment. The density of drug
io the peripheral compartment has not yet mched tht in the central compartmcnt.
Poixt 111: Distribution equilibrium h s been attained, and drug densitics in the
centd and periphed compartments arc appgoximately equal. Drug distribution in
both directioos contioucs to talze place, but the ratio of drug quantitics in toe centel
and peripheral compartments remains constant. At this point, the major determi-
nant of drug disappearance from thc central compartmcnt becomes the elimination
process; previously, drug disappearance W&S determined mainly by distribution.
Poi/s : During this elimination phase, the drug is being ‘-drained” from both com-

partmcnts out of the body (via the central companment) at approximatcly the same
rate. (Reproduced, with permission, from Grecnblatt DJ &nd Shader Rl, Phrma-
colsinetics in clinical practice, W.B. Saunders, Philadelphia. PA, 198S.)
TwoW M~
lo this input, wc soall apply mathematicaS principles to toe two-compartmcnt

model to calculatc useful poarmacokinetic parameters.
horo tiscussioo of the ooe-comparaneot model, we koow that the climination zte
coostant (J[) is estsmated fxm the slope of the lo pbsma coocentration vcrsus ame
curve. However, in a two-canzrg tnodel, wose the lo plasma coocentration versus
time curve is curvilinear, the slope varics, tepcndiog on waich porioo of toe curve
is cxamined (Flgurc 24A).
In a two compartment model, the tenninal slope from the pos,t-digributive phase of
the curve may bc backextrapolata~ to axnc zero (T). The oegative slope of this line
is teferret-to as beta (O, aot ,B is the tennioal eliminatton tate coostant of the trug.
The iotesept of this lioe on the In plasn coocentration axis is koown as B and is
uset in vanous two~cotnpeneot equations.
Bc~ is similtr to K in to t it vsents the tsminal elim meion r te constant. From it, a
half-life can be cal~ culS
T%, 0.693
is

which is refenet to as the “beta haSf-Ute. ‘
lEroughout the ame th_t trug is present in the boty, tistribuiion takes place between
the central ant peripheral compartmenu. We can calculate a ratc of tistribuaion
using the mct rcsidxals. This methot estim tes the cffect of distribution on the
ovcrall plasma concentration curvc and uses thc diZfcrcncc between thc cffect of
climination and thc actual plasma consentrations to determinc thc distribution rate.
In the In concentration versus vime curvc in Flgure 24A, the slope of the initial
portion is determined prim--arily by the distribution rate while thc tenninal portion
is determined primarily by thc climination rate.
E <~
100
50
S~
PodwDiattibutlon
Ph~
Timo Figsot 24A Plasma druy concentralions with a two-compartment model atter
an imravenous bolus do*c.

The methot of residuals may be used for calculating phamiacoMinctic parameters

of thc two-compartmcnt model. FuSst, b cl:-extrapolate the terminal straight-line
portion of tbe curve (Flgure 24B). If w, s. y, and 2 are actual, detennined concen-
tration time points, let w’, ~’, y’, and 2’ xpresent points on the new (extopolated)
line at the same times that tbe aaual points were obscrved. These newly generated
points xpresent the cffect of clim~ ination alone, as if distribution had been instan-
taneous. Subtnction of the extrapolated points from the corresponding actual
points (w—w’, X—~’, etc.) yields a new set of pbsma concenti-ation points for
each time point. If we plot tbese new points with the appmpriate times, we gener-
ate a new line, the “residual” line (hgure 24C).
The slope of tbe xsidual line is—st, and alpha (a) is the distribution rate constant
for the two-compartment system. The intrcept of the residual line is A. Therefore,
witb the coocept of residuals, we attempt to separate the two pwocsscs of diseribu-
tion and climin~ jon.
Ist us now pn~cood through an exampic, applying thc metbot of xsidtis. Draw tbc
plot for thc following cxampb on somilog gnph paper. A dosc of dnag is ad
10.0
50
‘ :!
Z c 10
—o
fL Q

Tlmo F~—241R Mcthod of xsiduals.
100
5e
Y’
Bz
~’
\ Sbpo = a
s -R
Timo
F; 24C Dctermination of the rcsidual linc.

62
InPtJT 24 63
ministered by rapid intravenous injection, and the tollowing concentrations result:
Tkne afttr
Dose (hr)
0.2S
O.S
1.0
I.S
2.0
4.0
8.0
12.0
16 0

Plasms
Concentration
(u~/ml)
43
32
20
14
11
6.S
2.8
1.2
0.S2
A linc is trawn connecting the last four points and intcnecting the y-axis. Then, for
the first five points, cxtrapolated values can be cstimated at cach time (0.2S, O.S,
1.0,’l.S, and 2.0 hr). If the extrapolated values from the actual plasma concentra-
tions are subtracted, a new set of points is generated (resitual concentration points)
as fts w~
Tlnse dir
Doz (hr)
0.2S
O.S

1.0
1.5
20
Pbsma Concentratlon (>g/ml)
^>e
Exupol ted Residud
14.S 28.S
13.S 18.S
12.3 7.7
1 1.0 3.0
!O.0 I.D
The zsidual concentrations are then plotted (on semilog paper) versus time, and the
slope of that plot equals —1.8 hr~t. When the negative is dropped, this slope
equals sx; we observe from the plot that the intercept (A) of the line is 4S Fg/ml.
We also can estimate a from the slope of the terminal straight-line portion (equal to
0.21 hr~ ~) and 8 (equal to IS 1lg/ml).
Alpha (ex) must be greater than beta (a), indicating that drug removal from plasma
by distribution into tissues proceeds at a greater rate than does drug removal from

plasma by eliminating organs (e.g., kidncys and liver). rhc initial portion of the
plot is steeper than the terminal portion.
REVIEW PR08LEMS
24.1. Dnw a log pbsma concentntion versus timc profile for a drug Oinimed by the
intravenous bolus nmute and best durizZ by a two-companrnent modeJ (Figure
24D).
242. Tbe slope of the tenninal phase of the above. plot equals
243. Tbe inucept of thc tenniial portion on tbe In pbsma concentstion axis is tenned
>.~ sca(g)~ tbe tenninal const nt of the dmg s it leaves the body.
24.S. One w y to calculatc a distnbution zate is to use tbe metbod of
24.C. Tbe fint step in the metaod of residuals is to.
- the telminal straight-line portioa of the curve. 24.7. The extryolatd points aw
subtmed from tbe actuaJ observed at the correspoading times.
24.8. Tbe slope of the residual line equals

24.9. “A” is tbeof tbe In
plasnu concenamtion axis by tbe
line.
2410. Tbe coocept of residuals attempts to separate tbe two
processes ofand—
100
• 50
ca e
Z c 10
FQ
Fkwe 24D
Tim
ljg

Two-Compartment Model-3
The estimations of A, 8, ss, ant t perforrned in tbe last input are useful for predic-
ing plasrrs concentotions of dmg ch~nzi by a two-compartrnent model. For
• awrst rnodel (Flgureo2SA), we know th t thc plaSsma concentration (C) t any

time (t) can be dessnbet by
Cf ^ Ce e t’
where CO is the initial concentration and g is ttne climination rate. Thae two-com-
partment rnodel (Flgure 2SB) is thc surn of two linear components, reprcsenting
distnbution ant elimination (Flgurc 2SC).
In thc sarnc w y, we can dctrminc dnag consentration (C) at ny tinx (t) by iding thc
two linear components. In cach casc, A or B i-s uset for CO, ant ex or z is used for
XY. Therefe
C, s ‘ +- 8 e~*’
ThiSs equation is called a •’biexponential cquation” bccausc two cxponents rc

iwaled. With thc onos

wrunt rnodcl (intravenous), wherc:
C. s Ce e ~’
2B
100
501
CO
10
Timo Fzwe 25A Pls dmg concentrations with a one com putment model aher an
insvenous bolus dose (first order elimination).
100
50
,o
z -, 10

~c
—o
Timc ft 25B Plasma drug concentrations with 3 two compartment model after an
intnvenous boluXs dose sfirst-order elimination) .
100
50
E; tO
Sz
Tlmo
Fw 25C lOr azmpo~s of a twozxpo~ (>
t) model.
~nentid” becausc thc linc is
t tnodel, diffcrcnt volume of
thc equation is

describet by onc exponents
E or thc twowrat dWibution psramctrs cxist thc centol volurnc {V¢), thc cxtrapo-
lated volunc (V,~ ,), tbc volunc by arca (V,,, also lcnown as V~|), ant thc stcadys-
tatc vohunc of diwibuX (V,,). Each of thcsc voluncs rclste to diffcrcat undertying
assumptioos.
As in thc onc-cornpenent rnotcl, a volunc can bc calculated by
V dose dox
¢ ,~ + B Co
For thc two-compartrnent model, this volurne would bc cquivalent to thc volumc
of the central compartment (V¢). Thc Ve rclates the amount of drug in thc-central
compartmcnt to the concentration in the central compartment. In thc two-compar-
trnent model, CO is determined by cxtrapolating back to thc y-axis from the upper
or initial straight-line portioo of the plot.
When we calculate the extrapolated volume of distribution (V,x,,,p), we assume

that instantaneous distribution has occurred. The effect of the iniial distribubon
phase is ignored:
da
V_

wherc B is the w-intetcept of thc line extrapolated from the terminal portion of the
curve. This volume of distribution determination may not provide a useful volume
term since it ovcrsimplifics the two-compartmcnt model and disregards thc distri-
bution phasc.
Another volumc (V,,O or V~) is detcrmined from the area under the plasma con-
centration vcrsus time curvc and thc tcrminal climination rate constant. This vol-
umc is related as follows:
114
lNvts S 65
vffi
dox CL
= —
ffi x AUC3
va

This calculation is not subject to thc ovcrsimplification of V,S,,p, but it is affected

by changes in clearance. The V,,,, relates the amount of drug in the body to the
concentration of drug in plasrna in the post-absorpion and postwdisttibuiion phase.
A ffnal volume tenn is the volume of disttibution at steady state (V,,). Although it
is not affected by changes in drug eliminadoo or ckarance, it is more difficult to
calculate. One way to estimate Vs, is to use the two compartment microconstants:
V,—Ve + ~’2vf
21
or it may be estimated by more complicated methods using AUC.
Since-different methods can be used to calculate the various volumes of distribu-

tion of a two-compartment model, you should always specify the metbod used.
When reading a pharrnacolcinetic study, pay particular attenion to the method for
calculating thc volume of distribution.
REVIEW PROBLEMS
2S.1. The terminal eliniination rate constant tn a twoaconF putment model is
2S.2. For the two-compurtment model. complete the equo tion describing the
relazionship of plasma concentration with time: C, - •

25.3. (True or False) The equation describing elimination afer an intravenous bolus
dose of a drug charauerized by a two-compartment model lequires two exponential
terms.
2!;.4. A patient is given a 500-mg dose of drug by intravenous injection and the
following plasma concentrations result:
Plssms
Time snerConcentrstion
Dese (hr)ItsSml)
Oo ss
0.7S
lS
,6
72.0
46.0
33.0
26.3
20.0

16.6
1r.2
9.0
5.0
_.7
n Rr
Plot the points on semilog paper Ithree cycle) and deterTnine the following: a. ~. b.
B. c. Residual concentrations for the first five points. d. A.
. t.
£ Prodictod Dlssma concentration at 1.2 hr after the
dose.
S- V,.
h. V,, (if AUC = 131.S mg/L x hr and dose SOO mg).
~ A#=W{~ SGS 2
PRi4CTlCE SET 2

The following pxbiems are for your xview. Dcfinitions of symbols ant Icey equa-
tions = pxvitet hc~:
k ~w climinton nte cowt
C, s pbSllk tn~ _—jUSt Aher a single inuvenous injectioQ
e - bese for the nxl log f~|eion - 2@71S
4 - nte of tose ~ion (msy be cxptesset as
milligsams per bour in the sense of a coQtinuous
infusion or u trug tose divitot by itifusion tune
for intemtittent infusions)
V • voluxne of tistribution
C_t - pcalc p1ssfu a ocentntis
C_ • tnmugn plsCOOCCD
a steaty state

a stcady st te t —duFn of intsvenous inAlsion
For muldpk dose, intennittent, intnvenous bolus injeciiOQ g stF st~
—k V (I - e~t’)
C_—Cw e~t’
For muletplffbse~ intctmiu, intnvenow itafi~ioo
C - t° (I ~ e t~)
—~ VK (I—e~tD
C_ - Cp e~tt~4
Fot contitiuous infusion before stee st te is reacbed:
C - V^°r (I - C-t’)
For continuous infusion t stcaty stac
C.4. 4
Vt Ws

PS2*1. A 60-kg patient is begun on a continuous intravenous infusion of theophyl-

line at 40 mgtbr. a Forty-eight hours after beginning ttte infusion, the plasma con-
centniion is 12 ~/ml (12 mg/L). If we assume that tbis COncentRtiOD is tbe stcady
state, wb t is the tbeoobylline clearansc?
b. If the volume of distribution is cstimated to be 30 L, what are the X and half-

life?
c. Since we kww V and t. what would the concentntion bc 10 hr aftcr beginning the
infusion?
d. ff the idision i continuet for 3 days ant then discondauet, what woult tD plamS
consentm tion be 12 hr ~r stopping the infwiont
e. If tne infusion is continuct for 3 d ys at 40 mg/ hr ant the stcaty-statc pluma con-
centtation is 12 Fg/tnl, WDat rate of trug infusion would liltely xsult sn a concen-
tradon of 18 ~/ml?
f. ARcr the iocosed infusion nte above is begun, how bog would it tic to tuch a plu
coo~ cenudon of 18 Fgiml?
PS2< A 60-log p ekat is st rted on 80 mS of gentunicin ewety 6 br in • I*br infu-

siagL
L If this pSt is us led to have an “avenge” V of 15 L ult a normal half-life of 3 hr,

wtuat will be the pealc plm coœcenttadon at stcady stuc?

b. After thc fifth tese. a peak plasma concentratlon (dsawn at thc ent of thc infu-
sion) is S Ag/ml ant thc ttnugh consentration (drawn right befott thc sixth tosc) is
0.9 Ag/ml. What is thc patient’s xtual gentamicin half-life? What is thc xtual vol-
ume of disvribution?
c. For this patient, what dosc should bc administen:d to reach a new steady-state
peak gentamicin concentration of 8 Fgiml? At this dosc. what will bc thc steady-
state trouQh concentration!
II_q
tFoD~ sU
~ Tvo-ConPart-ent Open Hodel
tatlente •ufferln~ chronle tenal fellure often require h _ odiolyele. Drug~ •cy be
~dxinletered by Injeetlon Into the wenoue •lde of the he odtcl~ser •~chine
Such e rituetlon vax ~ecerlbed by L tourneeu-Scheb •t •1 (Int. J. Clln. tharv col IS

116-120 {1972)) for •lx pctlente vho received •n introvenoue done ot gent _ letn
(90 ng). The neen etru- concentrctleno et sent~nicin (C~) •hovvd • blexponenttel
deellne vith tl t (t).
Ce t

(-~lllter)(oln)
o 60 10
5 75 20
5 25 lO
4 80 40
• 50 50
3 95 90
3 40 150
3 10 180
2 90 240
2 55 28S
o. Caleelete the ter lnal half-llfe (t~) the hybrid rete eonetento
•nd O •nd the coefflelente (~1 • 3 Sl) for gent- leln to theeo he-odlulyal~ putlente
b. tor •ubJecte vith noreel renal functlon. the •yete-le elearence (Cl~) of gentanletn
le •pproalaetel1 0.041 llter/ In. Sec uee 98X ef Cl~ le due to excretlon of
unchanged drug. renel tciluro utll ~rkedly effect ~ent~lcin clecr~nce.

Show vhether the petlent~ undergoinfS he odlelyele •xhlbit o nor-ol gentcnicln

•yett-le elexr~nce.
Calculete the two •pperent volune ot dletrtbut10n terwe (V •nd V )
•nd the ell fnetlon rete eonetont. Uhet frectton of tho gt ted eln ln the body •fter 3
hr nlght be la the peripherel ee part~ent7 At vh t tbae doee the gent _ Icin in the
peripherel ee pert~ent rench
~t
4. Under the eondittons of h odSxlyxte. coleulete the doxe tD) of
sentcoleln •tlSch vould be •dolaletered •very S hr {1) In order to ~alnteln •n

everogew •teady-ctete •erus concentretlon of 4 •g/llter.
•. Wlthout the hc odielyrer two ~ale petlente •ach •xhlbited • creetinine eleorence
(Cle ) of 5 •llwin; the norx~l velue le 117 t 20 •I/nin. A~using that the deereFeed
Clcr {e due to • decresce In glo-eruler filtretloo rcte vhst vould h-ve beeD the renel
clecrxnce (Clr) of gent~elcia In there two patlentn hed they rz cined vithout the he-
odlolysert Uhct done vould then need to be dsinletered every • hr to n Intoin (C~ •t
4 tert Co pcro your •eouer wStb tho thy~telea e Deek Refer neo.
Vancomycin is an antibiotic used in the treatment of endocarditis in patients aller-

gic to penicillin. It is poorly absorbed orally and acute pain is associated with inter-
muscular injection. I.V. is the route of choice. After a 1 gm I.V. dose the following
data is observed:

Time (hours)Concentration (mcg/ml)
.5 51
1.0 36
1.5 28
2.0 23
3.0 18.5
4o 16
6.0 12.5
8.0 99
12.0 6.25
FIND: a) A1 ;
b) alpha
c) Clearance ;
d) * of drug in peripheral compartment at equilibrium .
Clearance:

In normals, Erythromycin is cleared 90% by metabolism and 10% by the kidney.

Also, it is 90% protein bound at therapeutic levels. Welling and Creig (JPS 67,
1057-9,1978) reported an increase in the half life from 2.0 to 2.3 hours while also
reporting an increase in clearance from 275 to 485 ml/min and an increase in Vdss
from 57 to 100 litres when comparing normals to uremic patients. (Uremic patients
suffer from inveased concentration of urea as a result of severe renal failure.) A
physician has just called you and asked you to explain how he could have seen an
increase of 15% in the half life and a 75% increase in clearance at the same time
and what is the impact of this on antibiotic therapy for his uremic patient. In clear
concise English (not techno-bable), prepare a short written answer to this request.
Keep in mind that the man who requested the information is a medical professionat
intelligent, and very busy.
The following data was collected from a normal patient in the revious study (Well-
ing, op. cit.) following an IV bolus injection of 500 mg of erythromycin (as lacto-
bionate salt ).
time (hr)concentration (mcg/ml)timeconcentration
0 12 4 3 2.6
1 6.4 4 1.9
2 4.0 6 1.2
8 0.4
~.
Fmd the peak time in the peripheral compartment.the fraction of the drug in the
peripheral compartment at four hours.

Two compartment model
Spectinomycin (TROBICIN^TR^T) is an aminocyclitol antibiotic shown to be

active against most strains of NEISSERIA GONORRHOEAE at a minimum
inhibitory concentration of 20 mcg/ml. The usual adult dose is 2 g (4 g in areas of
known resistance) given I.M. through a 20 gauge needle. Initial studies were done
by the company to determine the pharmacokinetic parameters of the drug. The data
from a single IV Bolus dose of 0.5 g is as follows.
Time (minutes)Concentration
10 63
20 51
30 43
45 35
60 30
120 183
240 7.6
360 3.2
FIND:
(5 points) a) A^V1^V =
(5 points) b) B^V1^V =
(5 points) c) Clearance =

(5 points) d) t max in the peripheral compartment =
(10 points) e) % of drug in peripheral compartment at equilibrium =
Spectinomycin (TROBICINR) is an aminocyclitol antibiotic shown to be active

against most strains of NEISSERIA GONORRHOEAE at a minimum inhibitory
concentration of 20 mcg/ml. The usual adult dose is 2 g (4 g in areas of known
resistance) given I.M. through a 20 gauge needle. Initial studies were done by the
company to determine the pharmacokinetic parameters of the drug. The data from
a single IV Bolus
dose of 0.5 g is as follows.
Time (minutes)Concentration
10 63
20 51
30 43
45 35
60 30
120 18.3
240 7.6
360 3.2
b} B c) Ciearance d) t max in the peripheral compartment e) % of drug in periph-

eral compartment at equilibrium

The following information is offered from a 142 mg IV bolus dose of grisiofulvin

given to a 73 Kg man.
Time mcg/ml
1 1.67
2 1.22
3 .97
4 .83
6 .66
8 .56
12 .42
18 .27
24 .17
30 .11
Find A1, B1, alpha, beta, K10, K12, K21, Peak time in the peripheral
compartment, % in the peripheral compartment at equilibrium.
Can you assume that this drug can be estimated by a one compartment
model upon multiple dosing ?

Quinidine is current-ly used to treat ventricular and supraventricular arrythmias.- It

is available as a sulfate, gluconate, and polygalactouronate which contain 83%,
62* and 60* by weight free base (pRa 8.6). Qunidino sulfate is available in 200,
260, 300 and 325 mg tablets, while quinidine gluconate is available in 325 mg tab-
lets. The following pharnacokinetic parameters are reported by Ueda:
PARAMETER
C1 renal (ml/min/kg)
C1 hepatic (ml/min/kg) V1 (L/kg)
V beta (L/kg) F (oral)
t 1/2 alpha (min) t 1/2 beta (hr)
MTC (mic/ml) NEC (mic/ml)
Population Ave (+ SD)
0.93 (0.52)
3.26 (1.74)
0.66 (0.38)
2.61 (1.10)
0.71 (0.16)

6.69 (4.03)
6.44 (1.63)
8.53 (0.81)
* , 1.85 (0.19)
% bound to protein80.00(2.50)
During the last pharmacokinetic exam you noticed •ome cardiac problems.
Wh n you ch-cked with your physician, He prescribes quinidine. What
dose should you be on?
Later, he diagnoses mononucliosis from lack of sleep and poor •ating h bits •s weli
as cardiac arrythmias. Your liver funcion has dropped to 60* of normal. He pre-
scribes quinidine for you. What is the dose that you should be on ?
ie. -
ll-3
Quinidine is currently used to treat ventricular and supraventricular arrythmias. It

is available as a sulfate, gluconate, and polygalactouronate which contain 83%,
62% and 60% by weight free base (pKa 8.6). Qunidine sulfate is available in 200,

260, 300 and 325 mg tablets, while quinidine gluconate is available in 325 mg tab-
lets. The following pharmacokinetic parameters are reported by Ueda:
PARAMETERPopulation Ave (+ SD)
C1 renal (ml/min/kg)0.93 (0.52)
C1 hepatic (ml/min/kg)3.26 (1.74)
V1 (L/kg)0.66 (0.38)
V beta (L/kg)2.61 (1.10)
F (oral)0.71 (0.16)
t 1/2 alpha (min)6.69 (4.03)
t 1/2 beta (hr)6.44 (1.63)
MTC (mic/ml)8.53 (0.81)
MEC (mic/ml)1.85 (0.19)
% bound to protein 80.00 (2.50)
During the last pharmacokinetic exam you noticed some cardiac problems. When
you checked with your physician, He prescribes quinidine. What dose should you
be on?
Later, he diagnoses mononucliosis from lack of sleep and poor eating habits as
well as cardiac arrythmias. Your liver funcion has dropped to 60% of normal. He
prescribes quinidine for you. What is the dose that you should be on ?

Methotrexate is a cytolytic used for the treatment of acute leukemia and other
forms of cancer. After a a 400 mg/kg dose the following data was recorded for a 12
y/o boy.
Time (hours)
12
18
36
48
60
72
90
Concentration (mcg/ml) 360 70 15
1.2
0.46
0.36
0.15

bA) B c) Clearance d) % of drug in peripheral compartment at equilibrium
PROBLEM SET
zumper w~wFS
t L) v , ~ s D fv
Patients suffering chronic renal failure often require hemodialysis. Drugs may be
administered by injection into the venous side of the hemodialyzer machine.
Such a situation was described by L*tourneau-Saheb et al (Int. J. Clin. PKinma-

col., 15, 116-120 (1977)) for six patients who receivet an intravenous dose 7 gen-
tamicin (90 mg). The mean serum concentrations of gentamicin (Cs) showed a
biexponential decline with time (t).
(~9cyml) (mRn)
6.60 10
5-75 20
5.25 30
4.80 40
4.50 50
3.95 90
3.40 150

3.10 180
2.90 240
2.55 - 285
. .
(a) Calculate the values of t1/29 B, Bj, ~, A~, and V1. LFtourneau
Saheb et al reported,
tl/2 = 5.50 t 0.77 hr (mean i SD)
B s 0.0022 t 0.0004 min 1
B1 s 4.76 f 0.62 vg/ml
v • 0.053 t 0.009 min
A1 a 3.47 s 1.01 pg/ml
V1 s 11.3 ffi 2.0 litre
(b) Calculate C1 and VB
LFtourneau-Sahleb et al reported,
C1 s 40.8 t 7.8 ml/min
VB s 19.2 h 2.7 litre

_1
11-33
98X of the systemic clearance of gentamicin is composed of renal clearance-of

unchanged drug, so that renal failure woult severely alter gentamRcin systemic
clearance. In this case, the use of the hemodialyzer gave a systemic clearance close
to the 41.0 ml/min seen in patients with normal renal function.
(c) Under the conditions of hemodialysis, calculate the dose (D) of gentamicin
which would be administered every 8 hr (t) in order to maintain an Waverage”
steady-state serum concentration of 4 ug/ml. What would be (Cmax)ss and
(Cmin)ss?
(d) Without the hemodialyzer two male patients each exhibited a creatinine clear-
ance (Clcr) of S ml/min; the noW l value is 117 + 20 ml/min. Assuming that the
decreased ClCr is due to a decrease in glomerular filtration rate, what would have
been the renal clearance (Clr) of gentamicin in these two patients had they
remalned without the hemodialyzer? What dose would then need to be adminis-
tered every 8 hr to maintajn (~s) at 4 ug/ml? Compare your answer with the Physi-
cian’s Desk Reference (5677).
Your third patient comes from Edelman et al (Clin Pbarmacol Therap 35:382-6
(1984)). He studied metotrexate is artbritic patients. The pharmacokinetic parame-
ters gleened from the 10 mg IV data arc:
A1 (mg/L) 0.663 Alpha (hr-1) 059 B1 (mg/L) 0.073 Beta (hr-1) 0.097

15) What is the AUC (0 to inf) (mg / L * hr) ?
a) 0.75 b) 1.08 c) 1.12 d) 1.88e) 9.1
16) What is V1 (L) ?
a) 13.6 b) 15.1 c) 253 d) 36.1e)103.1
17) What is the clearance (L/hr) ?
a) 53 b) 8.9 c) 133 d) 15.4e) 17.2
18) What is V(beta) (L) ?
a) 13.6 b) 253 c) 36.1 d) 45e 55
19) What is the t(max) in the perepheral compartment (hr) ? a) 0 b) 1.8 c) 3.7 d) 5.1
e)6.1
20) What percent of the drug is in the perepheral compartment at cquilibrium ? a)

25 b) 50 c) 75 d) 100 e) 125
Two compartment: It has been proposed (Ionescu et al. Clin Pkin 14:178-
186,1988) that morphine injectcd dirtctly into thc spioal chord would give signifi-
cant analgesia. The following is a CSF concentration - time profile resulting from
05 mg/lcg IV bolus dose of Morphine:

time conc. time conc.
(min) (mg/L) (min) (mg/L)
2 251 120 323
5 181 240 173
10 142.5 360 82
20 1043 480 2.4
40 75.1 720 1.2
80 48.8
1 a) fraction of remaining drug contained in peripheral compartment at equilib-

rium. Lb) Can this drug be approximated by a one compartment model ? Support
your contention with calculations. Lc) Calculate a rcasonable dosage regimen for
the above patient to maintain the concentration within the therapeuticwindow of
50 to 5 mg/L.
Two compartment:
(1) It has been proposed that diazepam has anticonvulsant properties above 350
nanograms per milliliter. The following is a concentration - time profile resulting
from 10 mg IV bolus dose of diazepam :
time conc. time
(hrs) (ng/ml)(hrs)
0.25 480 6.0

0-50 400 8.0
l.o 300 10.0
2.0 170 16.0
3.0 120 24.0
on llo
l.a) fraction of remaining compartment at equilibrium.
n’
~_
conc.
(ng/ml)
100
90
85
70
53
Dlezzewm

UA tD 20A AD
Time
drug contained in peripheral
k21 = (1.05 * 116.8) + (0.0325 * 487.6) / (487.6 + 116.8)
= 138.5 / 604.4
= 0.239
klO = (1.05 * 0.0325) / 0.239
= n ls
kl2 = 1.05 + 0.0325 - 0.15 - 0.239
=n7
B2 = (0.7 * lOOOOmic) / (1.05 - 0.0325)
= 6880
V1 = lOOOOmic / 604.4 mic/l
= 16.55
X2 / total = 6880 / t6880 + (16.55 * 116.8mic/1)]

= 0.78
l.b) Can this drug be approximated by a one compartment model? Support your
contention with calculations.
AUC = (487.6 / 1.05) + (116.8 / 0.0325)
= 464.4 + 3594.8
= 4058.2
Since the beta phase contributes more than 80% of the total AUC, the model can
be collapsed to a one compartment model.
3594.8 / 4058.2 = 0.886 = 89%
l.c) Calculate a reasonable dosage regimen for the above patient to maintain the
concentration within the therapeutic window of 350 to 1100 nanograms per ml.
K = 1/MRT = 1 / (111007 / 4058.2) = 1/27.35 = 0.0253 per hr
t 1/2 = 0.693 / 0.0253 = 27.39 hr
2^N^ = 1100 / 350 = 3.14
N = ln 3.14 / ln 2 = 1.65

Tau max = 27.39 * 1.65 = 45.19 hr drop the dosing interval to 24 hours now need
to find a new N
N = 24 / 27.39 = 0.876
Vss = lOOOOmic / (4058.2mic*hr/1 * 0.0253/hr) = 97.25L
To find dose:
l.lOOmg/L = (D / 97.25 L) * tl / (1 - 0.5^0.876^)]
D = 49 mg daily (aggressive therapy)
0.350mg/L = (D / 97.25L) * t 1 / (1 - 0.5^0.876^)](0.5^0.876^)
D = 29 mg daily (conseervative therapy)
Therefore, any dose between 30 and 50 mg a day can be given.
Two Compartment:
We have used theophylline as a test drug in many of our calculations in class. We

assumed that it was a one compartment model. Look at the data from Mitenko
(Clin Pharmacol and Ther,14p509 1974) for intravenous theophylline (Dose 5.6
mg/kg):
sos

theophylilne
i ,_
1.
OD 2D 4wD 6D8S tD
Tlm~
Time (hr.)
0.167
0.333
0.500
0.833
1.0
1.5
2.0
3.0
4.0
6.0

8.0
Conc. (mg./L.)
24.7 Estimates of Pharmacokinetic parameters
20.3 are as follows:
18.1 A1 (mg/L)16.1
16.1 B1 (mg/L)17.9
15.6 Alpha (hr-l)4.8
14.3 Beta (hr-l)0.15
13.3 AUC (O to inf) 122.7
11. AUMC (O to inf) 797.6
9.8
7.3
s.4
1) What is the volume of the central compartment (L/Kg) ?

*A) 0.165 B) 0.30 C) 0.35 D) 2.9 E) 6.1
2) What is the clearance of theophylline (L/Kg/hr) ?
A) 0.007 *B) 0.046C) 2.7 D) 22 E) 142.4
3) What is the Volume of
distribution in the beta phase (Vbeta)
(L/Kg) ?
A) 0.165 *B) 0.30C) 0.35D) 2.9E) 6.1
4) What percent of the equilibrium ?
A) 12 B) 23
dose is in the peripheral compartment at
*C) 46 D) 69 E) 92 treated as a one compartment model for
5) Can theophylline be dosing purposes ?

A) No, a larger percentage of the drug is in the peripheral compartment.
B) NO, A1 and C) Yes, alpha D) Yes, the approximately
*E) Yes, the approximately
B1 are about the same value. is bigger than beta contribution of the alpha phase
AUC is the total AUC. contribution of the beta the total AUC.
phase AUC is
6) What is the mean residence time (MRT) for the IV dose (hr) ?
A) 4.25 B) 5 C) 5.75*D) 6.5E) 7.25
For the same dose of an oral product information was obtained:
AUC (O to inf)
AUMC (O to inf)
7) What is the MRT for the

A) 8.0 B) 8.75
122
1400
(TheoDur^TQ^T) the following
oral dose (hr) ?
C) 9.5 D) 10.25*E) 11.5
8) What is the mean absorption time (MAT) for the oral dose (hr)?
A) 1 B) 2 C) 3 D) 4 *E) 5
9) What is the absorption rate constant for theophylline in TheoDur
(hr^T-l^T) ?
A) 0.14 B) 0.17 *C) 0.2 D) 0.25 E) 0.3

Two compartment: The following pharmacokinetic information was obtained from

EA, a
45 y/o, 70 kg, healthy male following an800 mg IV dose of
vancomycin:
A1 60 mg/L
alpha 1.33 hr^-l
B1 20 mg/L
beta 0.129 hr^-l
AUC (mg/L * hr)200
AUMC (mg/L)1237
5) What is your patient’s vancomycin clearance(L/hr)?
a) 0.25 *b) 4 c) 24.74 d) 45.1 e) 155
6) What is your patient’s V(beta)(L)?
a) 10 b) 24.74 *c) 31 d) 45.1 e) 60

7) What is your patient’s V1(L)?
*a) 10 b) 24.74 c) 31 d) 45.1 e) 60
8) What is your patient’s MRT(iv) (hr)?
a) 0.112 b) 0.162 c) 1.39 d) 4.29 *e) 6.19
9) What is your patient’s effective rate of elimination (hr^-l)? a) 0.112 *b) 0.162 c)
0.5 d) 4.29 e) 6.19
10) What is your patient’s Vss (L)?
a) 10 *b) 24.74 c) 31 d) 45.1 e) 60
11) Following an IM dose of vancomycin, the MRT(im) was calculated to be 8.185

hr. What was the absorption half life (hr)? a) 0.112 b) 0.162 *c) 1.39 d) 2 e) 6.19
RP ‘s angina was controlled on 40 mg TID of propranolol. You calculated his phar-

macokinetic parameters to be: Vd (L) = 125; T1/2 (hr) = 3.1; Qh (L/hr) = 33; Bio-
availability (f) = .7; Bound(%) = 95. Propranolol is essen^_ tially 100%
metabolized.
12) What is his Total body clearance (L/hr)? a) 1.4 b) 14 *c) 28 d) 33 e)40.3

13) What is his hepatic extraction ratio?
a) 0.042b) .42 *c) .85 d) 1 e) 1.22
14) Assuming propranolol to be rapidly absorbed, what is his Cpss
max free concentration (ng/mL)?
*a) 13.4 b) 19.2 c) 188 d) 268 e) 355
15) What is his Cpss max total(bound and free) (ng/mL)?
a) 13.4 b) 19.2 c) 188 *d) 268 e) 355
16) What is his Cpss min free (ng/mL)?
*a) 2.2 b) 3.2 c) 31.4 d) 44.8 e) 59.3
He is now suffering from renal failure. His half life went up to 3.8 hr while his
binding went up to 98.3% because of an increase in AAG, a plasma protein to
which propranolol binds.

17) What is his new clearance (L/hr)?
a) 14.4 *b) 21.7 c) 24 d) 28 e) 36.2
18) What is his new volume of distribution (L)?
a) 79 *b) 119 c) 132 d) 153 e) 199
19) What will his new Cpss max free be if we keep him on the same
regimen (ng/mL)?
*a) 5.26 b) 7.5 c) 310 d) 442 e) 554
20) What is his new Cpss max total(ng/ml) ? a) 5.26 b) 7.5 *c) 310 d) 442 e) 554
21) What is his new Cpss min free (ng/mL)?
*a) 1.23 b) 1.75 c) 72.3 d) 103 e) 129

22) The physician sees that the clearance has dropped and consequently the total
plasma concentrations have gone up. He wants to decrease to dose to 40 mg / BID.
What would you recommend? a) Sounds good to me. That will get the Cpss max
total concentration back to it was before he was sick. b) His new clearance was
marginally changed because the drug is cleared by the liver. I’d leave it alone. c) I
think the change from TID to BID is a bit much. How about lowering it to 30 mg
instead of 40 mg TID. *d) We need to increase the dose, not lower it. I’d recom-
mend 40 mg QID. e) We need to increase the dose, not lower it. I’d recommend 80
mg QID.
Two compartment
Methotrexate is a cytolytic used for the treatment of acute leukemia and other
forms of cancer. After a a 400 mg/kg dose the following data was recorded for a 12
y/o boy.
Time (hours)Concentration (mcg/ml)
6 360
12 70
18 15
36 2
48 1.2
60 0.46
72 036
Q(} 0.15

FIND: (5 points) a) A^V1^V =
(5 points) b) B^V1^V =
(5 points) c) Clearance =
(5 points) d) % of drug in peripheral compartment at equilibrium =
Everything.
Primidone (Mysoline^T@^T) is an effective agent in the treatment of generalized

and complex partial seizures. Although primidone has anticonmlsant activity of its
own, much of the activity comes from the conversion to one of its metabolites,
phenobarbital. For the purposes of this exam, an insignificant error will be intro-
duced bytheuse of intermittent IV caSculations instead of oralformultipledose.
Thefolloving information for primidone and phenobarbital is available:
Primiflnne. Phenabarbital
Therapeutic Range (mg/L)5 - 12 10 - 30
Bioavailabiliq (f)1 0.9
Salt factor (S)1 09
Vd (L/Kg) 0.6 0.7
T1/2 7 hr 5 days
% Excreted undhanged2520
% Metabolized75 80

% Metabolized to Phenobarbital25*~
% Metabolized (non Phenobarb-paths)50**
2.(20 pts) Please prepare a short consult for your M.D. in which you caSculate a
dosage regimen for an 80 kg
patient whidh would l~eep the plasma concentration within the therapeutic range.
Prirnidone comes as 250 mg
scored (can be broken in half) tablets. Indude your average, maximum and mini-
mum primidone as well as
phenobarbital steady-state concentrations in the consult.
3. (25 pts) The patient recently contracted mono. His liver function has been
reduced to 50 % of normal.
Would you recommend a change in your therapy ? If you would, prepare a short
consult for his M.D. as in question #2. Don’t forget that changes in hepatic clear-
ance result in changes in both phenobarbital clearance 5~nfl fannation
4. (25 pts) Now that his mono has cleared up the doctor noticed that he has stenosis
of the liver as a consequence of all t_e heavy parting that he did after the kinetics
course. His liver plasma flow has been reduced to 50 % of normal. Would you rec-
ommend a dhange in therapy ? If you would, prepare a short consult for his M.D.
as in question #2. Don’t forget that dhanges in hepatic dearance result in changes
in both phenobarbital dearance and formation.


11.4 Begin

11.5 Problems

Aspirin (Problem 11 - 1)
Problem Submitted By: Maya Leicht AHFS 00:00.00
Problem Reviewed By: Vicki Long GPI: 0000000000
Fu, C., Melethil, S., and Mason, W., "The pharmacokinetics of aspirin in rats and the effect of buffer", Journal of Pharmacokinetics
and Biopharmaceutics, Vol. 19, (1991), p. 157 - 173.
Aspirin is an analgesic/ antipyretic commonly used to relieve minor pain and is used in such conditions as rheumatic
fever, rheumatoid arthritis, and osteoarthritis. The major metabolite of aspirin is salicylic acid. The following set of
data was collected using rats which weighed 250 - 300 g.
PROBLEM TABLE 11 - 1. Aspirin
weight of rat 275 g
Dose 5 mg/kg IV
A1 8.58
a 1.07
B1 7.24
b 0.2
AUC 38.8
AUMC 116.0
1. What is ?
2. What is ?
3. What is your patient's clearance?
4. What is your patients MRT?
5. What is your patient's ?
6. What is your patient's V1?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
13. What is ?
14. What is the in the peripheral compartment?
15. What percent of the dose is in the peripheral compartment at equilibrium?
16. Can this drug be treated as a one-compartment model for dosing purposes?
17. If this drug can be treated as a one-compartment model, what is K ?

Buprenorphine (Problem 11 - 2)
Ohtani, M., et al., "Pharmacokinetic analysis of enterohepatic circulation of buprenorphine and its active metabolite, norbu-
prenorphine, in rats", Drug Metabolism and Disposition, Vol. 22, (1994), p. 2 - 7.
Buprenorphine is a morphine derivative which has twice the duration of action and 30 times the potency of morphine.
Buprenorphine is partially metabolized to norbuprenorphine which is also active in the body. In this study, buprenor-
phine was given to rats weighing 280 - 300 g.
PROBLEM TABLE 11 - 2. Buprenorphine
Weight of rat 290 g
Dose 0.06 mg/kg IV
A1 41
a 3.89
B1 10
b 0.271
AUC 48.3
AUMC 135.24
1. What is the ?
2. What is the ?
3. What is the AUC?
5. What is your patients MRT?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
13. What is ?

17. If this drug can be treated as a one-compartment model, what is K ?

Caffeine (Problem 11 - 3)
Shi, J., et al., "Pharmacokinetic-pharmacodynamic modeling of caffeine: Tolerance to pressor effects", Clinical Pharmacology
and Therapeutics, Vol. 53, (1993), p. 6 - 14.
This study looks at the cardiovascular effects of caffeine. Caffeine is known to increase blood pressure upon its with-
drawl. This study looks at how tolerance to caffeine and its pressor effects develops and disappears with time.
PROBLEM TABLE 11 - 3. Caffeine
Patient weight 80 kg
Dose 4 mg/kg oral
A1 10.55
a 4.9
B1 9.1
b 0.23
f 98.4 %
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
13. What is ?

Cefazolin (Problem 11 - 4)
Nightingale, C., et al., "Changes in pharmacokinetics of cefazolin due to stress", Journal of Pharmaceutical Sciences, Vol. 64,
(1975), p. 712 - 714.
Cefazolin is a cephalosporin antibiotic used in the treatment of many types of infections. This study looks at the effect
of stress on the pharmacokinetics of cefazolin. The following data was approximated from the graph given in this arti-
cle.
PROBLEM TABLE 11 - 4. Cefazolin
Patient weight 56.3 kg
Dose 1 g IV
A1 206.48
a 4.832
B1 122.96
b 0.573
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Ceftazidime (Problem 11 - 5)
Ackerman, B., et al., "Effect of decreased renal function on the pharmacokinetics of ceftazidime", Antimicrobial Agents and Che-
motherapy, Vol. 25, (1984), p. 785 - 786.
Ceftazidime is a cephalosporin antibiotic. This study explores the effect of compromised renal function on the pharma-
cokinetics of ceftazidime. The following data was approximated from the graph given in this article.
PROBLEM TABLE 11 - 5. Ceftazidime
Dose 1 g IV bolus
A1 188
a 8.22
B1 58.2
b 0.49
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Clentiazem (Problem 11 - 6)
Shah, A., et al., "Pharmacokinetics of clentiazem after intravenous and oral administration in healthy subjects", Journal of Clini-
cal Pharmacology, Vol. 33, (1993), p. 354 - 359.
Clentiazem is an derivative of diltiazem which is under investigation for its use in the treatment of angina pectoris and
hypertension. Clentiazem blocks calcium channels resulting in a decrease in peripheral vascular resistance which sub-
sequently leads to a decrease in blood pressure.
PROBLEM TABLE 11 - 6. Clentiazem
Dose 20 mg IV bolus
A1 37.52
a 2.7
B1 16.17
b 0.078
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Cocaine (Problem 11 - 7)
Levine, B. and Tebbett, I., "Cocaine pharmacokinetics in ethanol-pretreated rats", Drug Metabolism and Disposition, Vol. 22,
(1994), p. 498 - 500.
This study looks into several reports which claim that the euphoric effects of cocaine can be enhanced when taken in
conjunction with alcohol. This effect may be the result of higher cocaine blood levels or a reduced elimination of
cocaine or a combination of both.
PROBLEM TABLE 11 - 7. Cocaine
Weight of rat 300 g
Dose 2 mg/kg cocaine (also 1 g/ kg ethanol)
A1 1172.6
a 0.362
B1 462
b 0.045
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

1,2-Diethyl-3-Hydroxypyridine-4-One (Problem 11 - 8)
Epemolu, O., et al., "The pharmacokinetics of 1,2-Diethyl-3-Hydroxypyridine-4-One (CP94) in rats, Drug Metabolism and Dispo-
sition, Vol. 20, (1992), p. 736 - 741.
1,2-Diethyl-3-Hydroxypyridine-4-One (CP94) is an iron chelator which is orally active. It is being investigated for use
in the treatment of hemoglobinopathic disorders. In this study, rats weighing 250 - 300 g were given doses 50 mg /kg
intravenously and the following data was collected:
PROBLEM TABLE 11 - 8. 1,2-Diethyl-3-Hydroxypyridine-4-One
Weight of rat 275 g
Dose 50 mg/kg IV
A1 30.9
a 2.03
B1 8.13
b 0.38
Assume that the rat ( which weighs 275 g) is suffering from thalassemia and his iron levels are very high. The rat is
prescribed CP94 to restore the iron levels to normal.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

2,2-dimethylaziridine (Problem 11 - 9)
Lalka, D., Jusko, W., and Bardos, T., "Reactions of 2,2-dimethylaziridine-type alkylating agents in biological systems II: Compar-
ative pharmacokinetics in dogs", Journal of Pharmaceutical Sciences, Vol. 64, (1975), p. 230 - 235.
The 2,2-dimethylaziridine alkylating agents are used for their antitumor capability as antineoplastic agents. In this
study, male mongrel dogs, weighing 20 - 28 kg, were each given a dose of 12 mg/kg of ethyl bis (2,2-dimethylaziridi-
nyl) phosphinate intraveneously.
PROBLEM TABLE 11 - 9. 2,2-dimethylaziridine
Weight of dog 24 kg
Dose 12 mg/kg IV
A1 42
a 0.409
B1 8.5
b 0.095
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Flurbiprofen (Problem 11 - 10)

Menzel-Soglowek, S., et al., "Variability of inversion of (R)-flurbiprofen in different species", Journal of Pharmaceutical Sciences,
Vol. 81, (1992), p. 888 - 891.
Flurbiprofen is an anti-inflammatory and analgesic agent. This study compares the pharmacokinetics of the (R)-isomer
of flurbiprofen to the those of the (S)-isomer. The following data was approximated from the graph given in this arti-
cle.
PROBLEM TABLE 11 - 10. Flurbiprofen
Weight of rat 260 g

Dose 10 mg/kg IV
A1 48.5
a 2.33
B1 57.68
b 0.175
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Furosemide (Problem 11 - 11)

Tilsone, W., and Fine, A., "Furosemide kinetics in renal failure", Clinical Pharmacology and Therapeutics, Vol. 23, (1978), p. 644
- 650.
Furosemide is an agent which is used for its diuretic action to treat such conditions as renal and cardiac edema. In this
study, normal subjects were given an intravenous bolus dose of 22 mg of furosemide. Blood samples were taken at var-
ious intervals and the following data was obtained:
PROBLEM TABLE 11 - 11. Furosemide
Dose 22 mg IV
A1 2.1
a 6.9
B1 0.77 -
b 0.96
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Glycyrrhizin (Problem 11 - 12)

Tsai, T., et al., "Pharmacokinetics of glycyrrhyzin after intravenous administration to rats", Journal of Pharmaceutical Sceinces,
Vol. 81, (1992), p. 961- 963.
Glycyrrhizin is a component of licorice which is proposed to have anti-inflammatory, anti-hepatotoxic, interferon-

inducing, anti-viral, and anti-ulcer activity. It also causes pseudoaldosteronism. The following data was approximated
from the graph given in this article.
PROBLEM TABLE 11 - 12. Glycyrrhizin
Weight of rat 275 g

Dose 20 mg/kg
A1 91.23
a 4.16
B1 69.90 -
b 0.43
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Human Deoxyribonuclease (Problem 11 - 13)

Mohler, M., et al., "Altered pharmacokinetics of recominant human deoxyribonuclease in rats due to the presence of a binding pro-
tein", Drug Metabolism and Disposition, Vol. 21, (1993), p. 71 - 75.
Deoxyribonucleases are found in human serum, urine, and a variety of tissues. These endonucleases catalyze the
hydrolysis of DNA to oligonucleotides. It has been suggested that increased levels of serum deoxyribonucleases may
predict malignancies.
PROBLEM TABLE 11 - 13. Human Deoxyribonuclease
Patient weight 260 g
Dose 1 mg/kg IV bolus
A1 19250 -
a 8.61
B1 4897
b 0.229
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Human Granulocyte Colony-Stimulating Factor (Problem 11 - 14)

Tanaka, H., and Kaneko, T., "Pharmacokinetic and pharmacodynamic comparisons between human granulocyte colony-stimulat-
ing factor purified from human bladder carcinoma cell line 5637 culture medium and recombinant human granulocyte colony-
stimulating factor produced in Escherichia coli", The Journal of Pharmacology and Experimental Therapeutics, Vol. 262, (1992),
p. 439 - 444.
Human Granulocye Colony-Stimulating Factor (hG-CSF) is used to stimulate the proliferation of precursor cells and
their subsequent differentiation in the bone marrow. This article compares the pharmacokinetics of hG-CSF produced
by two different methods. In the first method, the hG-CSF was obtained from human bladder carcinoma cell line 5637
culture medium. In the second method, the hG-CSF was produced by Escherichia coli.
PROBLEM TABLE 11 - 14. Human Granulocyte Colony-Stimulating Factor
Weight of rat 250 g
Dose 10 µg/kg IV
A1 116.21 -
0.24 hours
B1 99.228
1.27 hours
1. What is ?
2. What is ?
3. What is ?
7. What is a?
8. What is b?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Hydrocortisone (Problem 11 - 15)

Derendorf, H., et al., "Pharmacokinetics and oral bioavailability of hydrocortisone", Journal of Clinical Pharmacology, Vol. 31,
(1991), p. 473 - 476.
This study looks at both the two-compartment model pharmacokinetics and the oral bioavailability of hydrocortisone.
The following data was approximated from the graph given in this article.
PROBLEM TABLE 11 - 15. Hydrocortisone
Dose 20 mg IV
A1 430
a 13.1
B1 439 -
b 0.445
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Levodopa (Problem 11 - 16)

Sasahara, K., et al., "Dosage form design for improvement of bioavailability of levodopa II: Bioavailability of marketed levodopa
preparations in dogs and parkinsonian patients" Journal of Pharmaceutical Sciences, Vol. 69, (1980), p. 261 - 265.
Levodopa is an agent used in the treatment of Parkinson's disease. This study looks at various dosage forms of
levodopa and compares the pharmacokinetic parameters of each. The following data was approximated from the graph
given in this article.
PROBLEM TABLE 11 - 16. Levodopa
Dose 50 mg IV
A1 8.63
a 13.3
B1 2.97 -
b 1.14
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Meropenem (Problem 11 - 17)

Chimata, M., et al., "Pharmacokinetics of meropenem in patients with various degrees of renal function, including patients with
end-stage renal disease", Antimicrobial Agents and Chemotherapy, Vol. 37, (1993), p. 229 - 233.
Meropenem is a carapenem antibiotic which has a broad spectrum of activity. It is used in the treatment of infections
caused by both Gram-positive and Gam-negative bacteria and is active against Enterobacteriaceae and Pseudomonas
aeruginosa. Meropenem is 60% renally and 40% hepatically eliminated.
PROBLEM TABLE 11 - 17. Meropenem
Dose 500 mg IV infusion over 40 minutes

A1 21
a 1.85
B1 20 -
b 0.503
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

N-Methylpyridinium-2-Carbaldoxime Chloride (Problem 11 - 18)

Bodor, N., and Brewster, M., "Problems of delivery of drus to the brain", International Encyclopedia of Pharmacology and Thera-
peutics, Vol. 120, (1975)
N-methylpyridinium-2-cabaldoxime chloride (2-PAM) is the drug of choice for the treatment of orgaonphosphate poi-
soning. It is mostly renally excreted. This article considers the fact that this agent is highly hydrophilic and thus has
difficulty reaching the brain. The following data was approximated from the graph given in this article.
PROBLEM TABLE 11 - 18. N-Methylpyridinium-2-Carbaldoxime Chloride
Weight of dog 40 kg
Dose 7.0 mg/kg
A1 5.356
a 0.28796
B1 35.983
b 11.586
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Pyrazine Diazohydroxide (Problem 11 - 19)

Vogelzang, N., et al., "Phase I and pharmacokinetic study of a new antineoplastic agent: pyrazine diazohydroxide (NSC 361456)",
Journal of Cancer Research , Vol. 54, (1994), p. 114 - 119.
Pyrazine diabhohydroxide is an agent which forms a reactive pyrazine dizonium ion in vivo which acts to destroy
tumor cells. This study looks at the pharmacokinetic parameters of this agent in advanced cancer patients whose cancer
was not curable by any other type of therapy. They were given a dose of 18 mg/m2/day for 5 days every 4 weeks.
Most of the following data was collected for a 66 year old male subject. The remaining data was approximated from
the graph given in this article.
PROBLEM TABLE 11 - 19. Pyrazine Diazohydroxide
Patient Body Surface Area 1.82 m2
Dose 18 mg/ m2
A1 8063
a 0.195
B1 1186
b 0.0257
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Terbinafene (Problem 11 - 20)

Kovarik, J., et al., "Dose-proportional pharmacokinetics of terbinafine and its N-demethylated metabolite in healthy volunteers",
British Hournal of Dermatology, Vol. 126, (1992), p. 8 - 13.
Terbinafene is an antifungal agent which acts by interfering with ergosterol biosynthesis. It is active against Tricho-
phyton, Epidermophyton, and Microsporum. Approximately 70% of an oral dose is absorbed. Terbinafene has an N-
demethylated metabolite which is active. The following data was approximated from the graph given in this article.
PROBLEM TABLE 11 - 20. Terbinafene
Dose 750 mg
A1 2398
a 0.511 -
B1 102 -
b 0.0222 -
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Verrucarol (Problem 11 - 21)

Barel, S., Yagen, B., and Bailer, M., "Pharmacokinetics of the trichothecen mycotoxin verrucarol in dogs", Journal of Pharmace-
tuical Seciences, Vol. 79, (1990), p. 548 - 550.
Verrucarol is a toxin which is related to toxins which have anti-tumor activity. This study looks at the pharmacokinet-
ics of verrucarol in dogs. The following data was approximated from the graph given in this article.
PROBLEM TABLE 11 - 21. Verrucarol
Weight of Dog 22.5 kg

Dose 0.4 mg/ kg
A1 126.05
a 0.0415
B1 540.58 -
b 0.00946-
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

2-Chloro-2-deoxyadenosine (Problem 11 - 22)

Liliemark, J. and Juliusson, G., "On the pharmacokinetics of 2-Chloro-2-deoxy-adenosine in humans", Cancer Research, Vol. 51,
(1991), p. 5570 - 5572.
Two-Chloro-2-deoxyadenosine is an antitumor agent used in the treatment of hairy cell leukemia and other lymphopro-
liferative diseases. Infusions of 0.14 mg/kg over 12 hours were administered to 12 patients with various lymphoprolif-
erative diseases for 5 consecutive days. The following data was collected:
PROBLEM TABLE 11 - 22. 2-Chloro-2-deoxyadenosine
Dose 0.14 mg/kg over 12 hours
A1 177.0 nM
a 1.04
B1 21.0 nM
b 0.10
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Felodipine (Problem 11 - 23)

Regardh, C., et al., "Pharmacokinetics of felodipine in patients with liver disease", Journal of Clinical Pharmacology, Vol. 36,
(1989), p. 473 - 479.
The pharmacokinetic parameters of felodipine in patients with impaired liver function were investigated in this study.
Felodipine blocks calcium channels resulting in a decrease in peripheral vascular resistance which subsequently leads
to a decrease in blood pressure. Felodipine also works as a diuretic. The bioavailability of felodipine is 15%. It is
highly (99.64%) protein bound and is eliminated almost exclusively by liver metabolism. The following data is for a
patient with liver cirrhosis:
Weight of dog kg
Dose mg/kg IV
A1
a
B1
b
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Lorazepam (Problem 11 - 24)

Segal, J., et al., "Decreased systemic clearance of lorazepam in humans with spinal cord injury", Journal of Clinical Pharmacol-
ogy, Vol. 31, (1991), p. 651 - 656.
Lorazepam is a benzodiazepine which is used as an anxiolytic, an anti-convulsant, an anti-emetic, and a sedative-hyp-

notic agent.
PROBLEM TABLE 11 - 24. Lorazepam
Dose 2.0 mg infused intravenously over 1 - 2 minutes

A1
a
B1
b
AUC
AUMC
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Metronidazole (Problem 11 - 25)

Uccellini, D., Morgan, D., and Raymond, K., "Relationships among duration of infusion, dose, dosing interval, and stedy-state
plasma concentrations during intermittent intravenous infusions: studies with metronazole", Journal of Pharmacokinetics and
Biopharmaceutics, Vol. 14, (1986), p. 95 - 106
PROBLEM TABLE 11 - 25. Metronidazole
Dose 1.5 g IV infusion
A1
a 2.11
B1
b 0.09
AUC
AUMC
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

Rhizoxin (Problem 11 - 26)

Graham, M., et al., "Preclinical and phase I studie with rhizoxin to apply a pharmacokinetically guided dose-escalation scheme",
Journal of the National Cancer Institute, (1991), p. 494 - 499.
Rhizoxin is a lactone which was obtained from the fungus, Rhizopus chinensis. It has anti-tumor activity
against a broad spectrum of tumor types including LOX melanoma, A549 lung tumors, and MX-1 mammary
tumors. This study looks at dosing of rhizoxin. Patients with nontreatable tumors who had a life expectancy
of more than 12 weeks were given doses of 12 mg/ m2. The following data was approximated from the
graph given in this article.
PROBLEM TABLE 11 - 26. Rhizoxin
Patient Body Surface Area 1.82 m2

Dose 12 mg/ m2
A1 1.55
a 4.00
B1 0.12
b 0.116 -
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?

11.5.1 TWO-COMPARTMENT MODEL EQUATIONS

The following set of equations were used to solve the two-compartment model problem set. The problem sets for the
first three drugs have been done for you. The others are done the same way. The answers for all of the problems are in
the back of this packet.
Aspirin
1.
2.
3.
4.
5. The weight of the rat is 275 g or 0.275 kg.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15. Yes
_____________________________________________________________________
Buprenorphine
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.

12.
13.
14.
15. Yes
_____________________________________________________________________
Caffeine
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15. Yes
11.5.2 ANSWERS
Aspirin
1. 8.019
2. 36.2
3. 31.1
4. 2.62 minutes
5. 155.48 mL
6. 86.92 mL
7. 81.57 mL

8. 0.648 min
9. 3.47 min
10. 0.598 min-1
11. 0.358min-1
12. 0.314min-1
13. 15.82
14. 1.928 minutes
15. 44.1%
16. Yes
17. 0.381 min-1
Buprenorphine
1. 10.54
2. 36.9
3. 47.4
4. 366.8
5. 2.85 hours
6. 1.35 L
7. 0.34 L
8. 0.178 hours
9. 2.58 hours
10. 0.981 h-1
11. 1.075 h-1
12. 2.11 h-1
13. 51
14. 0.736 hours
15. 74.9%
16. No
17. Can't be calculated
Caffeine
1. 2.15
2. 39.57
3. 41.72

4. 7.67
5. 33.35 L
6. 16.28 L
7. 0.141 hours
8. 3.014 hours
9. 2.39 h-1
10. 0.471 h-1
11. 2.266 h-1
12. 19.65
13. 0.655 hours
14. 51.2%
15. Yes
Cefazolin
1. 42.73
2. 214.59
3. 257.32
4. 3.89
5. 6.78 L
6. 3.035 L
7. 0.143 hours
8. 1.21 hours
9. 2.163 h-1
10. 1.28 h-1
11. 1.96 h-1
12. 329.44
13. 0.50 hours
14. 55.2%
15. Yes
Ceftazidime
1. 22.87
2. 118.78

3. 141.65
4. 7.0598
5. 14.41 L
6. 4.06 L
7. 0.0843 hours
8. 1.415 hours
9. 2.32 h-1
10. 1.738 h-1
11. 4.65 h-1
12. 246.2
13. 0.365 hours
14. 39.2%
15. Yes
Clentiazem
1. 13.9
2. 207.3
3. 221.2
4. 90.4
5. 1159.2 L
6. 372.5 L
7. 0.257 hours
8. 8.89 hours
9. 0.868 h-1
10. 0.243 h-1
11. 1.67 h-1
12. 53.69
13. 1.35 hours
14. 47.4%
15. Yes
Cocaine
1. 3239.2
2. 10266.7

3. 13505.89
4. 44.43
5. 987.2 mL
6. 367.1 mL
7. 1.91 minutes
8. 15.4 minutes
9. 0.1346 min-1
10. 0.1210 min-1
11. 0.1514 min-1
12. 1634.6
13. 8.35 minutes
14. 59.2%
15. No
1,2-Diethyl-3-hydroxpyridine-4-one
1. 15.22
2. 21.39
3. 36.62
4. 375.5
5. 988.2 mL
6. 352.3 mL
7. 0.341 hours
8. 1.824 hours
9. 0.724 h-1
10. 1.066 h-1
11. 0.62 h-1
12. 39.03
13. 1.016 hours
14. 55.4%
15. No
2,2-dimethylaziridine
1. 102.7
2. 89.47

3. 192.16
4. 1498.7
5. 15.78 L
6. 5.7 L
7. 1.695 minutes
8. 7.296 minutes
9. 0.148 min-1
10. 0.263 min-1
11. 0.093 min-1
12. 50.5
13. 4.65 minutes
14. 56.5%
15. No
Flurbiprofen
1. 20.82
2. 329.6
3. 350.42
4. 7.42
5. 42.4 mL
6. 24.5 mL
7. 0.297 hours
8. 3.96 hours
9. 1.35 h-1
10. 0.303 h-1
11. 0.856 h-1
12. 106.18
13. 1.2 hours
14. 42.2%
15. Yes
Furosemide
1. 0.304
2. 0.802

3. 1.106
4. 19.88
5. 20.71 L
6. 7.67 L
7. 0.1005 hours
8. 0.722 hours
9. 2.55 h-1
10. 2.59 h-1
11. 2.71 h-1
12. 2.87
13. 0.322 hours
14. 62.99%
15. No
Glycyrrhizin
1. 21.93
2. 162.56
3. 184.5
4. 29.8
5. 69.33 mL
6. 34.13 mL
7. 0.167 hours
8. 1.61 hours
9. 2.048 h-1
10. 0.873 h-1
11. 1.67 h-1
12. 161.13
13. 0.61 hours
14. 50.8%
15. Yes
Human Deoxyribonuclease
1. 2235.78
2. 21384.3

3. 23620.1
4. 11.01
5. 48.07 mL
6. 10.77 mL
7. 0.0805 hours
8. 3.027 hours
9. 1.929 h-1
10. 1.0223 h-1
11. 5.89 h-1
12. 24147
13. 0.433 hours
14. 28.9%
15. Yes
Human Granulocyte Colony-Stimulating Factor
1. 40.24
2. 181.81
3. 222.05
4. 11.26
5. 20.62 mL
6. 11.6 mL
7. 2.89 h-1
8. 0.546 h-1
9. 1.625 h-1
10. 0.971 h-1
11. 0.839 h-1
12. 215.44
13. 0.711 hours
14. 43.8%
15. Yes
Hydrocortisone
1. 32.8
2. 986.5

3. 1019.3
4. 19.62
5. 44.1 mL
6. 23.01 mL
7. 0.053 hours
8. 1.56 hours
9. 6.838 h-1
10. 0.853 h-1
11. 5.85 h-1
12. 869
13. 0.267 hours
14. 47.8%
15. Yes
Levodopa
1. 0.649
2. 2.61
3. 3.25
4. 15.37
5. 13.48 L
6. 4.31 L
7. 0.052 hours
8. 0.61 hours
9. 4.25 h-1
10. 3.56 h-1
11. 6.62 h-1
12. 11.6
13. hours
14. 68.0%
15. Yes
Meropenem
1. 11.35
2. 39.76

3. 51.11
4. 9.78
5. 19.45 L
6. 12.20 L
7. 0.375 hours
8. 1.378 hours
9. 1.16 h-1
10. 0.802 h-1
11. 0.391 h-1
12. 41
13. 0.967 hours
14. 37.3%
15. No
N-methylpyridinium-2-carbaldoxime chloride
1. 18.6
2. 3.106
3. 21.71
4. 12.9
5. 1.11 L
6. 6.77 L
7. 2.41 hours
8. 0.0598 hours
9. 1.752 h-1
10. 1.905 h-1
11. 8.218 h-1
12. 41.339
13. 0.327hours
?14. 45.5%
15. Yes
Pyrazine Diazohydroxide
1. 41348.7
2. 46147.9

3. 87496.6
4. 0.3744
5. 14.57 mL
6. 3.542 mL
7. 3.55 minutes
8. 26.97 minutes
9. 0.0474 min-1
10. 0.106 min-1
11. 0.0676 min-1
12. 9249
13. 11.97 minutes
14. 75.7%
15. No
Terbinafene
1. 4692.8
2. 4594.6
3. 9287.4
4. 80.75
5. 3637.6 L
6. 300 L
7. 1.36 h
8. 31.2 h
9. 0.0421 h-1
10. 0.2692 h-1
11. 0.222 h-1
12. 2500
13. 6.42 hours
14. 91.8%
15. No
Verrucarol
1. 3037.35
2. 57143.8

3. 60181.1
4. 149.5
5. 15.81 L
6. 13.5 L
7. 16.7 minutes
8. 73.3 minutes
9. 0.0155 min-1
10. 0.0253 min-1
11. 0.0101 min-1
12. 666.63
13. 46.15 minutes
14. 28.1%
15. Yes


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CHAPTER 11 Multicompartment Modeling

Author: Michael Makoid

Basic Pharmacokinetics REV. 99.4.25 11-1

11.1 Executive Summary

Basic Pharmacokinetics REV. 99.4.25 11-2

Basic Pharmacokinetics REV. 99.4.25 11-3

11.3 PHARMCOKINETICS: MAMMILLARY MODELS

Compartnent Two (peripheral compartment) cannot normally be sampled. It may

The Body is the sum of both compartments.

Basic Pharmacokinetics REV. 99.4.25 11-4

1. Biexponential Properties of Two-Compartment Open Model

Following an intravenous bolus injection, the plasma concentration against time

a. Initial phase - ( α - phase)

b. Terminal phase - ( β - phase)

2. Intravenous Bolus Administration: Plasma Concentration Data

For a one-compartment open model,

For a two-compartment open model,

Basic Pharmacokinetics REV. 99.4.25 11-5

V 1 is the apparent volume of unchanged drug distribution in compartment one

2.2 Relationships (for reference, except Eq. 3)

Basic Pharmacokinetics REV. 99.4.25 11-6

2.3 Obtaining Pharmacokinetic Parameters by “Feathering”

a. Plot C p against t on semilogarithmic paper

b. Find t 1 ⁄ 2 from the linear terminal phase: see “Intravenous Administration”,

Basic Pharmacokinetics REV. 99.4.25 11-7

e. Read estrapolated plasma concentrations ( C p ) from the plot at times equal to

f. At each of these times calculate:

g. Plot ( C p )diff against t (see Eq.8) on semilogarithmic paper. The is a “feath-

Basic Pharmacokinetics REV. 99.4.25 11-8

j. Calculate ( C p )o from Eq. 3

The extrapolated plasma concentrations are

Substituting from Eqs. 2 and 7a into Eq. 5,

Basic Pharmacokinetics REV. 99.4.25 11-9

Note (for reference only)

2.4 Clearance and Volume

If model-independant equations can be used to define these terms, this is preferred.

a. Systemic Clearance (Cl) may be calculated by,

Basic Pharmacokinetics REV. 99.4.25 11-10

The apparent volume of distribution in compartment one ( V1 )

This is calculated using Eq. 6.

The apparent volume of distribution at pseudo-distribution equilibrium ( V β )

c. Comparing Eqs. 9 and 10,

Basic Pharmacokinetics REV. 99.4.25 11-11

It may also be shown that,

Cl = k 10V 1 (EQ 10-36)

This is a model-independent equation.

Basic Pharmacokinetics REV. 99.4.25 11-12

2.6 Dosage Regimens

The maintenance dose (D) is given by the same model-independent equation as

Where ( C p )ss has its same previous definition.

Note (reference only)

All dosage regimen equations strictly apply only when,

Basic Pharmacokinetics REV. 99.4.25 11-13

For digoxin Eq. 17 has a value of 0.947

For warfarin Eq. 17 has a value of 0.990

For cephalexin Eq. 17 has a value of 0.846

3. Intravenous Bolus Administration: Compartment Two

It is not normally possible to measure drug concentrations in compartment two.

2.6 Dosage Regimens

Basic Pharmacokinetics REV. 99.4.25 11-14

This is comparted to the mass modification of Eq. 7,

4. Others Dosage Forms

4.1 Intravenous Infusion