Pharmacokine

tics
 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
 within large aqueous
compartments
 across tight junctions
 across endothelium thru pores
(MW20,000 - 30,000)
 molecules tend to move from an
area of higher to an area of
lower concentration
 plasma protein-bound drugs
cannot permeate thru aqueous
pores
 charged drugs will be influenced
by electric fields
 Lipid diffusion
 higher partition coefficient =
easier for a drug to enter lipid
phase from aqueous
 charged drugs – difficulty in
diffusing thru lipid
 uncharged – lipid-soluble
 lower pH relative to pKa,
greater fraction of protonated
drug (protonated form of an
acid is neutral; protonated
form of a base is charged)
 A weak acid at acid pH & a
weak base at alkaline pH will
be more lipid-soluble
 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
page break . . . .
 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 transferas substrate Example
e
Glucuron- Glucuroni Glucurony Phenols, Morphine
idation c acid l alcohols, acetaminop
transferas carbolic hen
e acids, diazepam
hydroxylami digitoxin
nes, meprobama
sulfonamides te

Acetylatio Acetyl N-Acetyl- Amines Sulfonamid

n CoA transferas es isoniazid
e clonazepam
dapsone
mescaline
Reaction Reactant transfera substrate Example
se
Sulfate Phospho- Sulfo- Phenols, Estrone
conjugati adenosyl transfera alcohols, warfarin
on phospho- se aromatic acetaminop
sulfate amines hen
methyldopa

methylati S- Trans- Catecholami Dopamine

on adenosyl methylas nesphenols, epinephrine
methioni es amines histamine
ne 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
that’s all for now. . .