Jenny B.

Jimenez, BSMT
3A

Pharmacokinetics
Component Processes
 Absorption – entry of a drug from its site of administration to
the systemic circulation
 Distribution – process by which a drug enters the interstitium
or tissues from the blood
 Metabolism / Biotransformation – processes by which a drug
is changed: to its active form or to its removable form
 Excretion – removal of the drug from the body
 Drug Biodisposition
Drug

Absorption into Plasma

Distribution to
Tissue Tissues
Sites of
Storage Bound Drug Action

Free Drug

Drug Metabolism: Liver, Lung, Drug Excretion: Renal, Biliary,

etc etc.
 Permeation
 Permeation – travel of a drug across cellular
membranes, influencing its biodisposition; is
dependent on:
Solubility
Ionization
Concentration gradient
Surface area
Tissue vascularity
 Solubility
 Lipid solubility - ability to diffuse through lipid bilayers
 Water solubility – in aqueous phases
 Partition Coefficient: The ratio of lipid solubility to aqueous
solubility. The higher the partition coefficient, the more
membrane soluble is the substance.
 Ionization
 Drugs are weak acids or weak bases, & can exist in
nonionized or ionized forms in an equilibrium, depending on
pH & pKa. The Henderson–Hasselbalch equation determines
the percentage of ionization (ionized – water-soluble;
nonionized – lipid-soluble)
 Ionization increases renal clearance of drugs
 Concentration gradient – diffusion is down a concentration
gradient
 Surface area – the larger the surface area, the better the
permeation
 Tissue vascularity – the better the vascularity, the better the
permeation
 Absorption
 Passive diffusion – most common
Aqueous diffusion: Fick’s Law:

Flux (J) = (C1 – C2) x S.A. x P. coefficient

Thickness
 J = molecules per unit time
 C1= higher concentration
 C2 = lower concentration
 S.A. = surface area available for diffusion
 P. Coefficient = permeability coefficient / partition coefficient
 Thickness = length of the diffusion path
 Absorption
Lipid diffusion: the Henderson–Hasselbalch equation
log (protonated / unprotonated) = pKa – pH
*for acids: pKa = pH + log x concentration [HA] unionized
concentration [A]
*if [A] = [HA], then pKa = pH + log (1); log (1) = 0, so
pKa = pH
*for bases: pKa = pH + log x concentration [BH+] ionized
concentration [B]
*if [B] = [BH+], then pKa = pH + log (1); log (1) = 0, so
pKa = pH
 weak Acids & weak Bases
 A weak acid is a neutral molecule that dissociates into an
anion & a proton (H+) so that its protonated form is neutral,
more lipid-soluble
 A weak base is a neutral molecule that can form a cation by
combining with a proton so its protonated form is charged,
water-soluble

weak acids pKa weak bases pKa

Phenobarbital 7.1 Cocaine 8.5
Pentobarbital 8.1 Ephedrine 9.6
Acetaminophen 9.5 Chlordiazepoxide 4.6
Aspirin 3.5 Morphine 7.9
 Diffusion
Aqueous diffusion Lipid diffusion
within large aqueous compartments
higher partition coefficient
across tight junctions = easier for a drug to
enter lipid phase
across endothelium thru pores (MW20,000 - from
30,000)
aqueous
molecules tend to move from an area of higher to an
area of lower concentration charged drugs – difficulty
in diffusing thru lipid
plasma protein-bound drugs cannot
 permeate thru
aqueous pores uncharged – lipid-soluble
lower
charged drugs will be influenced by pH relative
electric fields to pKa,
greater fraction of
protonated drug
(protonated form of an
acid is neutral;
protonated form of a base
is charged)
 Special Carriers
Facilitated diffusion – passive (no E expended)
carrier-mediated transport.
saturable;
subject to competitive & non-competitive inhibition
used by peptides, amino acids, glucose
Active (uses E) carrier-mediated transport
saturable
subject to competitive & non-competitive inhibition
against a concentration gradient
 e.g. Na – K pump
 Endocytosis & Exocytosis
ENDOCYTOSIS
 entry into cells by very large substances
(uses E)
 e.g. Iron & vit B12 complexed with their
binding proteins into intestinal mucosal cells
EXOCYTOSIS
 expulsion of substances from the cells into
the ECF (uses E)
 e.g. Neurotransmitters at the synaptic
junction
 Ion Trapping
 Ion trapping or reabsorption – delays excretion
 Kidneys:
 nearly all drugs are filtered at the glomerulus
 most drugs in a lipid-soluble form will be reabsorbed by
passive diffusion
 to increase excretion: change urinary pH to favor the charged
form of the drug (not readily absorbed)
– weak acids are excreted faster in alkaline pH (anion form favored)
– weak bases are excreted faster in acidic pH (cation form favored)
 Other sites: body fluids where pH differs from blood pH, favoring
trapping or reabsorption
 stomach contents ▪ aqueous humor
 small intestines ▪ vaginal secretions
 breast milk ▪ prostatic secretions
 Distribution
 First pass effect – decreased bioavailability of drugs
administered orally because of initial absorption into
the portal circulation & distribution in the liver where
they may undergo metabolism or excretion into bile
 Extraction Ratio – magnitude of the first pass effect.
ER = cl Liver / q (hepatic blood flow)
 Systemic drug bioavailability – determined from
extent of absorption & ER.
F = f x (1 – ER)
 Distribution
Volume of Distribution – ratio between the
amount of drug in the body (dose given) & the
concentration of the drug in blood plasma. Vd
= drug in body / drug in blood
Factors influencing Vd:
drug pKa (permeation)
extent of drug-plasma protein binding
lipid solubility (partition coefficient)
patient age, gender, disease states, body composition
 Drug – Plasma Protein Binding
 Most drugs are bound to some extent to plasma
proteins Albumin, Lipoproteins, alpha 1 acid
glycoprotein
 Extent of protein binding parallels drug lipid
solubility
 Binding of drug to Albumin is often non-selective,
 Acidophilic drugs bind to Albumin, basophilic drugs
bind to Globulins
 drugs with similar chemical/physical properties may
compete for the same binding sites
 Volume of distribution is inversely proportional to
protein binding
 Distribution
 Non-ionized (hydrophobic) drugs cross
biomembranes easily
 Binding to plasma proteins accelerates absorption
into plasma but slows diffusion into tissues
 Unbound / free drug crosses biomembranes
 Competition between drugs may lead to displacement
of a previously bound drug  higher levels of
free/unbound drug  better distribution
 Distribution occurs more rapidly with high blood
flow & high vessel permeability
 Distribution
 Special barriers to distribution:
 placenta
 blood-brain barrier
 Many disease states alter distribution:
 Edematous states – cirrhosis, heart failure, nephrotic syndrome –
prolong distribution & delay Clearance
 Obesity allows for greater accumulation of lipophilic agents within
fat cells, increasing distribution & prolonging half-life
 Pregnancy increases intravascular volume, thus increasing
distribution
 hypoAlbuminemia allows drugs that normally bind to it to have
increased bioavailability
 Renal failure may decrease drug bound fraction (metabolite
competes for protein binding sites) & thus ↑ free drug levels
 Blood Brain Barrier (BBB):
Only lipid-soluble compounds get through the BBB.
Four components to the blood-brain barrier:
 Tight Junctions in brain capillaries
 Glial cell foot processes wrap around the capillaries
 Low CSF protein concentration ------> no oncotic pressure for
reabsorbing protein out of the plasma.
 Endothelial cells in the brain contain enzymes that metabolize,
neutralize, many drugs before they access the CSF.
– MAO and COMT are found in brain endothelial cells. They
metabolize Dopamine before it reaches the CSF, thus we
must give L-DOPA in order to get dopamine to the CSF.
  Exceptions to the BBB. Certain parts of the brain are not
protected by the BBB:
 Pituitary, Median Eminence
 Supraventricular areas
 Parts of hypothalamus
 Meningitis: It opens up the blood brain barrier due to edema.
Thus Penicillin-G can be used to treat meningitis (caused by
Neisseria meningitides), despite the fact that it doesn't normally
cross the BBB. Penicillin-G is also actively pumped back out of
the brain once it has crossed the BBB.
 Sites of Concentration: can affect the Vd
 Fat, Bone, any Tissue, Transcellular sites: drug concentrates in
Fat / Bone / non-Plasma locations  lower concentration of drug
in Plasma  higher Vd
 Metabolism
Biotransformation of drugs (usually in the Liver; also in the
Lungs, Skin, Kidney, GIT)) to more polar, hydrophilic,
biologically inactive molecules; required for elimination from
the body.
 Phase I reactions – alteration of the parent drug by exposing a
functional group; active drug transformed by phase I reactions
usually lose pharmacologic activity, while inactive prodrugs
are converted to biologically active metabolites
 Phase II reactions – parent drug undergoes conjugation
reactions (to make them more soluble) that form covalent
linkages with a functional group: glucuronic acid, acetyl coA,
sulfate, glutathione, amino acids, acetate, S-adenosyl-
methionine
 Metabolism
Phase I
 reaction products may be directly excreted in urine or react
with endogenous compounds to form water-soluble conjugates
 mixed function oxidase system (cytochrome P450 enzyme
complex: Cyt P450 enzyme, Cyt P450 reductase) requires
NADPH (not ATP) as E source, & molecular O2; [drug
metabolizing enzymes are located in hepatic microsomes:
lipophilic, endoplasmic reticulum membranes (SER)]
 Phase I enzymes perform multiple types of reactions:
 OXIDATIVE REACTIONS
 REDUCTIVE REACTIONS
 HYDROLYTIC REACTIONS
CYTOCHROME-P450 COMPLEX:
 There are multiple isotypes.
 CYT-P450-2, CYT-P450-3A are responsible for the metabolism of most drugs.
 CYT-P450-3A4 metabolizes many drugs in the GIT, decreasing the
bioavailability of many orally absorbed drugs.
 INDUCERS of CYT-P450 COMPLEX: Drugs that increase
the production or ↓ degradation of Cyt-P450 enzymes.
 Phenobarbital, Phenytoin, Carbamazepine induce CYT-P450-3A4
 Phenobarbital, Phenytoin also induce CYT-P450-2B1
 Polycyclic Aromatics (PAH): Induce CYT-P450-1A1
 Glucocorticoids induce CYT-P450-3A4
 Chronic Alcoholism, Isoniazid induce CYT-P450-2E1. important! this drug
activates some carcinogens e.g. Nitrosamines.
*Chronic alcoholics have up-regulated many of their CYT-P450 enzymes.
 INHIBITORS of CYT-P450 COMPLEX
 Inhibit production: Ethanol suppresses many of the CYT-P450
enzymes, explaining some of the drug-interactions of acute
alcohol use.
 Non–competitive inhibition: Chloramphenicol is metabolized by
Cyt P450 to an alkylating metabolite that inactivates Cyt P450
 Competitive inhibition: Erythromycin inhibits CYT-P450-3A4.
Terfenadine (Seldane) is metabolized by CYT-P450-3A4, so the
toxic unmetabolized form builds up in the presence of
Erythromycin. The unmetabolized form is toxic and causes lethal
arrhythmias. This is why Seldane was taken off the market;
Cimetidine, Ketoconazole – bind to the heme in Cyt P450,
decreasing metabolism of Testosterone & other drugs
Steroids: Ethinyl estradiol, Norethindrone; Spironolactone;
Propylthiouracil (PTU): inactivate Cyt P450 by binding the heme
 Metabolism
Phase II
 Drug Conjugation reactions: “detoxification” rxns: non-
microsomal, primarily in the liver; also in plasma & GIT –
usually to glucuronides, making the drug more soluble.
 conjugates are highly polar, generally biologically inactive
(exception: morphine glucuronide – more potent analgesic
than the parent compound) & tend to be rapidly excreted in
urine or bile
 “Enterohepatic recirculation”: high molecular weight
conjugates are more likely to be excreted in bile  intestines,
where N flora cleave the conjugate bonds, releasing the parent
compound into the systemic circulation delayed parent drug
elimination & prolongation of drug effects
 conjugation, hydrolysis, oxidation, reduction
Reaction Reactant transferase substrate Example
Glucuron- Glucuronic Glucuronyl Phenols, Morphine
idation acid transferase alcohols, acetaminophen
carbolic acids, diazepam
hydroxylamines, digitoxin
sulfonamides meprobamate
Acetylation Acetyl CoA N-Acetyl- Amines Sulfonamides
transferase isoniazid
clonazepam
dapsone
mescaline
Glutathione Glutathione GSH- S- Epoxides, nitro Ethacrynic acid
conjugation transferase groups, bromobenzene
hydroxylamines
Reaction Reactant transferase substrate Example

Sulfate Phospho- Sulfo- Phenols, Estrone

conjugation adenosyl transferase alcohols, warfarin
phospho- aromatic acetaminophen
sulfate amines methyldopa

methylation S-adenosyl Trans- Catecholamines Dopamine

methionine methylases phenols, amines epinephrine
histamine
thiouracil,
pyridine
 Toxicity
 drugs are metabolized to toxic products
 hepatotoxicity exhibited by
acyl glucuronidation of NSAIDS
N-acetylation of Isoniazid
Acetaminophen in high doses – glucuronidation &
sulfation are usual conjugation reactions in therapeutic
doses, but in high doses, these get saturated so Cyt
P450 metabolizes the drug, forming hepatotoxic reactive
electrophilic metabolites  fulminant hepatotoxicity &
death (antidote: N-acetylcysteine)
 Reduction in Bioavailability
First pass effect
Intestinal flora metabolize the drug
Drug is unstable in gastric acid e.g. Penicillin
Drug is metabolized by digestive enzymes e.g.
Insulin
Drug is metabolized by intestinal wall
enzymes e.g. sympathomimetic drugs /
catecholamines
 Excretion
 Clearance – CL – removal of drug from the blood, or
the amount of blood/plasma that is completely freed
of drug per unit time over the plasma concentration of
the drug
CL = rate of elimination of drug
plasma drug concentration
 especially important for ensuring appropriate long-term dosing, or
maintaining correct steady state drug concentrations
 Renal clearance - unchanged drug, water-soluble metabolites –
glomerular filtration, active tubular secretion, passive tubular
reabsorption of lipid-soluble agents
 Hepatic clearance – extraction of drugs after GIT absorption
 Excretion
 Half life (t ½) – time required to decrease the amount
of drug in the body by 50% during elimination or
during a constant infusion; useful in
 estimating time to steady-state: approximately 4 half-lives to
reach 94%
 Estimation of time required for drug removal from the body
 Estimation of appropriate dosing interval: drug accumulation
occurs when dosing interval is less than 4 half-lives
Affected by
 Chronic renal failure – decreases clearance, prolongs half-life
 increasing Age – Vd changes, prolongs half-life
 Decreased plasma protein binding shortens half-life
 Drug Elimination
 Zero order kinetics – rate of elimination of the drug
is constant regardless of concentration i.e. constant
amount of drug eliminated per unit time so that
concentration decreases linearly with time
examples: ethanol, phenytoin, aspirin
 First order kinetics – rate of elimination of the drug
proportional to concentration i.e. constant fraction of
the drug eliminated per unit time so that
concentration decreases exponentially over time
 Excretion
 KIDNEY
 GLOMERULAR FILTRATION: Clearance of the apparent volume
of distribution by passive filtration.
 Drug with MW < 5000 ------> it is completely filtered.
 Inulin is completely filtered, and its clearance can be
measured to estimate Glomerular Filtration Rate (GFR).
 TUBULAR SECRETION: Active secretion.
 Specific Compounds that are secreted:
– para-Amino Hippurate (PAH) is completely secreted, so its
clearance can be measured to estimate Renal Blood Flow
(RBF).
– Penicillin-G is excreted by active secretion. Probenecid can
be given to block this secretion.
 Anionic System: The anionic secretory system
generally secretes weak ACIDS:
– Penicillins, Cephalosporins
– Salicylates
– Thiazide Diuretics
– Glucuronide conjugates
 Cationic System: The cationic secretory system
generally secretes BASES, or things that are
positively charged.
 Ion-Trapping: Drugs can be "trapped" in the urine,
and their rate of elimination can be increased, by
adjusting the pH of the urine to accommodate the
drug. This is useful to make the body get rid of
poisons more quickly.
– To increase excretion of acidic drugs, make the urine
more basic (give HCO3-)
– To increase excretion of basic drugs, make the urine
more acidic.
 BILIARY EXCRETION: Some drugs are actively secreted in the
biliary tract and excreted in the feces. Some of the drug may be
reabsorbed via the enterohepatic circulation.
 Transporters: The liver actively transporters generally large
compounds (MW > 300), or positive, negative, or neutral
charge.
– Anionic Transporter: Transports some acids, such as Bile
Acids, Bilirubin Glucuronides, Glucuronide conjugates,
Sulfobromophthalein, Penicillins
– Neutral Transporter: Transports lipophilic agents, such as:
» Steroids
» Ouabain
 Cationic Transporter: Transports positively charged agents, such
as n-Methylnicotinamide, tubocurarine
 Charcoal can be given to increase the fecal excretion of these
drugs and prevent enterohepatic reabsorption.
 Cholestyramine can be given to increase the rate of biliary
excretion of some drugs.
ORDERS of EXCRETION:
ZERO-ORDER EXCRETION: The rate of excretion of a
drug is independent of its concentration.
 General properties:
– dC/dt = -K
– A plot of the drug-concentration -vs- time is linear.
– The half-life of the drug becomes continually shorter as
the drug is excreted.
 Examples:
– Ethanol is zero-order in moderate quantities, because
the metabolism system is saturated. The rate of
metabolism remains the same no matter what the
concentration.
– Phenytoin and Salicylates follow zero-order kinetic at
high concentration.
  FIRST-ORDER EXCRETION: The rate of excretion of a drug is directly
proportional to its concentration.
 General properties:
– dC/dt = -K[C]
– A plot of the log[conc] -vs- time is linear. slope of the line = -Kel / 2.303
– The half-life of the drug remains constant throughout its excretion

 HALF-LIFE: The half-life is inversely proportional to the Kel, constant of

elimination. The higher the elimination constant, the shorter the half-life.
COMPARTMENTS:
One-Compartment Kinetics: Kinetics are calculated
based on the assumption that the drug is distributed to
one uniform compartment.
 One compartment kinetics implies that the drug
has a rapid equilibrium between tissues and the
blood, and that the release of the drug from any
tissues is not rate-limiting in its excretion.
 One-compartment kinetics also assumes that the
drug is distributed instantaneously throughout the
body. This is only true for IV infusion.
Multi-Compartment Kinetics: Most drugs follow multi-
compartment kinetics to an extent.
 Biphasic Elimination Curve: Many drugs follow a
biphasic elimination curve -- first a steep slope
then a shallow slope.
– STEEP (initial) part of curve ------> initial distribution of
the drug in the body.
– SHALLOW part of curve ------> ultimate renal excretion
of drug, which is dependent on the release of the drug
from tissue compartments into the blood.
CLEARANCE: The apparent volume of
blood from which a drug is cleared per unit of
time.
CLEARANCE OF DRUG = (Vd)x(Kel)
 The higher the volume of distribution of the drug,
the more rapid is its clearance.
 The higher the elimination constant, the more rapid
is its clearance.
  This is based on the Dilution Principle:
– (Conc)(Volume) = (Conc)(Volume)
– Total Amount = Total Amount
MEANING: In first-order kinetics, drug is cleared at a
constant rate. A constant fraction of the Vd is cleared
per unit time. The higher the Kel, the higher is that
fraction of volume.
 Drug Clearance of 120 ml/min ------> drug is
cleared at the same rate as GFR and is not
reabsorbed. Example = inulin
 Drug clearance of 660 ml/min ------> drug is
cleared at the same rate as RPF and is actively
secreted, and not reabsorbed. Example = PAH
 BIOAVAILABILITY: The proportion of
orally-administered drug that reaches the
target tissue and has activity.
  AUCORAL = Area under the curve. The total amount of drug,
through time, that has any activity when administered orally.
 AUCIV = Area under curve. The total amount of drug,
through time, that has any activity when administered IV. This
is the maximum amount of drug that will have activity.
 100% Bioavailability = A drug administered by IV infusion.
 BIOEQUIVALENCE: In order for two drugs to be bioequivalent,
they must have both the same bioavailability and the same
plasma profile, i.e. the curve must have the same shape. That
means they must have the same Cmax and Tmax.
 Cmax: The maximum plasma concentration attained by a drug-
administration.
 Tmax: The time at which maximum concentration is
reached
 REPETITIVE DOSES:
 FLUCTUATIONS: Drug levels fluctuate as you give each dose.
Several factors determine the degree to which drug levels
fluctuate.
 There are no fluctuations with continuous IV infusion.
 Slow (more gradual) absorption also reduces fluctuations,
making it seem more like it were continuous infusion.
 The more frequent the dosing interval, the less the
fluctuations. Theoretically, if you give the drug, say, once
every 30 seconds, then it is almost like continuous IV
infusion and there are no fluctuations.
 Steady-State Concentration (CSS): The plasma concentration of
the drug once it has reached steady state.
 It takes 4 to 5 half-lives for a drug to reach the steady state,
regardless of dosage.
– After one half-life, you have attained 50% of CSS. After two
half-lives, you have attained 75%, etc. Thus, after 4 or 5 half-
lives, you have attained ~98% of CSS, which is close enough
for practical purposes.
 If a drug is dosed at the same interval as its half-life, then the
CSS will be twice the C0 of the drug.
– If you have a drug of dose 50 mg and a half-life of 12 hrs, and
you dose it every 12 hrs, then the steady-state concentration
you will achieve with that drug will be 100 mg/L.
 – D: Dose-amount. The higher the dose amount, the
higher the Css.
 : Dosage interval. The shorter the dosage interval, the higher
the Css
– F: Availability Fraction. The higher the availability
fraction, the higher the Css.
– Kel: Elimination Constant. The higher the elimination
constant, the lower is the Css.
 Vd: Volume of Distribution. A high volume of distribution
means we're putting the drug into a large vessel, which means
we should expect a low Css.
– Cl: Clearance. The higher the drug-clearance, the lower
the Css.
 – If you know the desired steady-state concentration and
the availability fraction, then you can calculate the dosing
rate.
 LOADING DOSE: When a drug has a long half-life, this is a
way to get to CSS much faster.
 Loading Dose = twice the regular dose, as long as we are giving the drug at
the same interval as the half-life.

 INTRAVENOUS INFUSION: The CSS is equal to the input

(infusion rate x volume of distribution) divided by the output
(Kel)
  R0 = the rate of infusion.
 Vd = the volume of distribution, which should be
equal to plasma volume, or 3.15L, or 4.5% of TBW.
 Kel = Elimination Constant
Loading Dose in this case is just equal to
Volume of distribution time
 RENAL DISEASE: Renal disease means the drug is not
cleared as quickly ------> the drug will have a higher Css
------> we should adjust the dose downward to accommodate
for the slower clearance.
 If the fraction of renal clearance is 100% (i.e. the drug is cleared only by the
kidneys), then you decrease the dosage by the same amount the clearance is
decreased.
 For example: If you have only 60% of renal function remaining, then
you give only 60% of the original dose.
 If the fraction of renal clearance is less then 100%, then multiply that fraction
by the percent of renal function remaining.
 For example: If you have only 60% of renal function
remaining, and 30% of the drug is cleared by the kidney, then
the dose adjustment = (60%)(30%) = 20%. The dose should
be adjusted 20%, or you should give 80% of the original dose
  G = The percentage of the original dose that we should give
the patient.
 If G = 60%, then we should give the patient 60% of
the original dose.
 f = The fraction of the drug that is cleared by the kidney.
 If f is 100%, then the drug is cleared only by the
kidney.
 ClCr = Creatinine clearance of patient, and normal
clearance. The ratio is the percent of normal kidney function
remaining.
 Renal disease increases the time to reach steady-state
concentration. Renal Disease ------> longer half-life ------> longer
time to reach steady-state.