Pharmacokinetic

s
 Component
Processes
 Absorpti on– entry of a drug from its site
of administration to the systemic
circulation
 Distributi on– 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
 Excreti on– removal of the drug from the
 Drug Biodisposition /
PharmacokineticsDrug

ABSORPTION into Plasma

DISTRIBUTION
Tissue to Tissues
Sites of
Storage Bound Drug Action

Free Drug

Drug METABOLISM: Drug EXCRETION:

Liver, Lung, etc Renal, Biliary, etc.
 Permeatio
n
 Permeation – travel of a drug across
cellular membranes, influencing its
biodisposition; is dependent on:
Solubility

Ionization

Concentration gradient

Surface area
 Drug
 Solubility Permeation
 Lipid solubility – ability to pass through lipid bilayers
 Water solubility – in aqueous phases
 Partition coefficient – ratio of lipid to aqueous solubility : the higher
the partition coeff, the more membrane soluble the drug

 Ionization
 The Henderson–Hasselbach equation – determines the percentage
of ionization (ionized=water-soluble; nonionized=lipid-soluble)
 Drugs are either weak acids or weak bases, & can exist as charged
or neutral particles in equilibrium, depending on pH & pKa
 Ionization increases renal clearance of drugs
 Drug
Permeation
Concentration gradient – diffusion is downa
concentration gradient; the greater the
concentration gradient, the faster the
diffusion/permeation
 Surface area – the available area for
permeation; the greater the surface area, the
faster the diffusion / permeation
 Tissue Vascularity – density of blood supply &
speed of blood flow – the better/more the tissue
vascularity, the better the permeation
 Absorptio
 Passive diffusion n
– most common
Aqueous diffusion: Fick’s Law:

Flux (J) = ( C 1 – C2) x

S.A.x P .
 effi
co J = molecules
c ie nt per unit time
 C1= higher concentration Thick
 C2 = lower concentration ness
 S.A. = surface area available for diffusion
 P. Coefficient = permeability coefficient / partition coefficient
 Thickness = length of the diffusion path
 Absorptio
n
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
 weakAcids & weak
B
 A weak acid a
iss
aeneutral
s 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
 Diffusio
 Aqueous diffusion n  Lipid 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
 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
 Carrier – mediated
Transport
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
 Ion trapping or Trapping
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
 stomachor reabsorption
contents ▪aqueous humor
 small intestines ▪vaginal secretions
 breast milk ▪prostatic
secretions
 Distributio
n
 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)
 Distributio
n
 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
 MostBinding
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
 Distributio
n
 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
 Distributio
 Special barriers n
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
 BloodBrainBarrier(BBB):
Onlylipid-solublecompoundsgetthroughtheBBB.
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
 Metaboli
sm(usually in the Liver; also in the
Biotransformati onof drugs
Lungs, Skin, Kidney, GIT)) to more polar, hydrophilic,
biologically inactive molecules; required for elimination
from the body.
 PhaseIreacti ons – 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
 P h a s e I r e a c ti o n s – 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
 Metabolis
PhaseI m
 reaction products may be directly excreted in urine or
react with endogenous compounds to form water-soluble
conjugates
 mixedfuncti onoxidasesystem (cytochrome P450
enzyme complex: C y t P 4 5 0 e n z y m e , C y t P 4 5 0
reductase) requires NADPH(not ATP) as E source, &
molecularO2;[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
 Metaboli
PhaseI
sm
 Drug Conjugati onreacti ons:“detoxifi cati on”rxns:non-
microsomal, primarily in the liver; also in plasma & GIT
– usually to glucuronides, making the drug more
soluble.
 conjugatesare highlypolar, generally biologically
inactive(exception: morphine glucuronide – more potent
analgesic than the parent compound) & tend to be
rapidlyexcretedin urine or bile
 “Enterohepaticrecirculation”: high molecular weight
conjugates are more likely to be excreted in b i l e 
intestines, where N floracleave the conjugate bonds,
releasing the parent compound into the systemic
circulation delayed parent drug elimination &
p r o l o n ga ti o n o fd r u g e f e c t s
 conjugati on,hydrolysis,oxidati on,reducti on
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
transferase groups,
conjugation hydroxylamines bromobenzene
Reaction Reactant transferase substrate Example

Sulfate Phospho- Sulfo- Phenols, Estrone

conjugation adenosyl transferase warfarin
alcohols, acetaminophen
phospho- methyldopa
sulfate aromatic
amines
methylation S-adenosyl Trans- Catecholamines Dopamine
methylases phenols, amines
methionine epinephrine
histamine
thiouracil,
pyridine
 Toxici

ty
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
 Excretio
n
 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
 Excretio
n
 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.
 Excretio
 Half life ( t ½ )
n
– 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
 Half –
Life
The half-life is inversely proportional to the
Kel, constant of elimination. The higher
the elimination constant, the shorter the
half-life.
 Drug
Elimination
 Zeroorderkinetics – rate of elimination of the
drug is constant regardless of concentration i . e .
constant amountof drug eliminated per unit
time so that concentration decreases linearly
with time
examples: ethanol, phenytoin, aspirin
 Firstorderkinetics – rate of elimination of the
drug proportional to concentration i.e.constant
fracti onof the drug eliminated per unit time so
that concentration decreases exponentially over
time
that’s all for now. .
.