Pharmacokinetics

Pharmacokinetics
Quantitative study of drug movt in, thru and
out of the body

Absorption
Distribution
Metabolism / Biotransformation
Excretion

What the body does to the drug

Pharmacokinetics
Biological membrane
Bilayer (abt 100 A thick) of phospholipids and
cholesterol
the polar groups (glyceryl phosphate attached
to ethanolamine / choline or hydroxyl group of
cholesterol) at the 2 surfaces
Nonpolar hydrocarbon chains in the matrix to
form a continuous sheet
Extrinsic and intrinsic protein molecules are
adsorbed on the lipid bilayer
 Extrinsi
c
Protein

Carbohydra
te

Phospholipi Intrinsic
d Protein
Pharmacokinetics
Drug transport across membranes

1. Passive diffusion and filtration

Passive diffusion
- along conc gradient
- pH influence
 Passive Diffusion

Rate depends on:

Lipid : water partition
coefficient
Concentration gradient
 Passive diffusion
Influence of pH:
Most drugs are weak electrolytes

So their ionisation is pH dependent

Weakly acidic drugs (e.g. aspirin)

ionise more in alkaline pH

Weakly basic drugs (e.g.

quinine)ionise more in acidic pH

Unionised form is more lipid soluble

 Passive diffusion
pH (Cont.)
Hence acidic drugs accumulate on
the more basic side of the membrane

pH= pH=
1.4 7.4
HA HA

A- + A- +
H+ H+
 Passive diffusion
5. pH (Cont.)
Acidic
drugs absorbed from
stomach

After entering gastric mucosal cell

this drug ionizes ion trapping

Acidic drugs excreted faster in

alkaline urine
 Filtration
Passage of drugs through pores in
the membrane

Depends on:
Pore size

Rate of flow of solvent

Carrier Mediated Transport
Properties:
Specific

Saturable

Competitively inhibited by analogs

Ionophores Substances which transport

ions
Pharmacokinetics
Carrier mediated
a)Facilitated diffusion SLC transporters eg.
glucose into muscle and fat cells by GLUT4

b) Active transport
i. Primary - ABC transporters eg Pgp
ii. Secondary
- another set of SLC transporters - OATP, OCT
- energy to pump one solute derived from downhill
movt of another
- symport / cotransport & antiport/exchange
transport
A. Facilitated Diffusion
B. Active Transport

ATP
Pinocytosis
Absorption
Movt of drug from its site of administration to
circulation

Factors affecting absorption

1. Aqueous solubility
- disintegration time (particle size)
- dissolution time
2. Conc
3. Area of absorbing surface
4. Vascularity of the absorbing surface
5. Route of administration
 Absorption
Disintegration time & dissolution rate
Solid dosage form
disintegration
Fine particles
dissolution
Solution

Absorption
Absorption
Route of administration
A) Oral
- nonionised, lipid soluble drugs
- increased gastric emptying increased absn ---
increased villi
- presence of food (Ca with tetracycline)
- degradation by acid - Pen G (enteric coated ,
sustained release)
- extrusion by P-gp eg digoxin
- concurrent admn of other drugs
- alteration of gut flora by antibiotics
- malabsorption
Absorption
Route of admn
B) S.C and I.M.
- heat application / exercise

- vasoconstriction; hyaluronidase increases

absn (s.c.)

- depot preparations eg. Benzathene penicillin

Absorption
Route of administration
C) Topical sites
- lipid soluble and ability to penetrate intact
skin
- abraded surface
- occlusive dressing increased hydration
- eye-drops absn thru NL duct
- mucous memb lipid - soluble
Absorption
Bioavailability

Rate and extent of absn of a drug from a

dosage form

Fraction (F) of administered dose that

reaches systemic circulation in unchanged
form
Absorption
Bioavailability
WHY?

Oral
- incomplete absn
- 1st pass metabolism
s.c. or i.m.
-local binding
Measurement of
Bioavailability

Plasm
a Conc

Time

BIOAVAILABILITY= AUC(oral) 100

AUC (i.v.)
Absorption
Chemical equivalence
Bioequivalence
Therapeutic equivalence
Why?
Diluents, stabilising agents, binders, lubricants

affect disintegration
Particle size, solubility, crystal form, other physical properties

affect dissolution
Absorption
Difference in bioavailability mostly seen with
poorly soluble and slowly absorbed drugs :
- decrease in particle size (microfine tabs)
increase rate of absn of aspirin
- griseofulvin and spironolactone microfined
- no need to decrease particle size of freely
water-sol drugs eg. PCM

Practical significance digoxin (low safety

margin), oral hypoglycemics, oral anticoagulants
(dosage needs precise control)
DISTRIBUTIO
N
Movement of drug molecule
from the blood to the tissue
Distribution
After absn, drug passes thru several body
compartments depending on its
physicochemical properties.

They are:
Plasma
Interstitial fluid compartment
Transcellular fluid compartment eg. fluids in
the GIT, bronchi, CSF
Intracellular fluid compartment
Distribution
Factors affecting drug distribution
Lipid solubility
Ionisation at physiological pH
Extent of binding to plasma and tissue prot
Presence of tissue-specific transporters
Differences in regional blood flow

Movt proceed till equilibrium established b/w

unbound drug in plasma and tissue fluids, then
parallel decline in both due to elimination
Distribution
Apparent volume of distribution (V)
The volume that would accommodate all the
drug in the body, if the conc throughout was
the same as in plasma
V= dose administered i.v.
plasma concentration
Lipid insol drugs poor cell entry V ECF vol
High lipid sol drugs high V
High PPB low V
Distribution
If a drug does not crosses capillary walls
and is given by i.v route its V is equal to
plasma volume

Drugs highly bound to plasma protein

have a low V value

V for many drugs may be much more than

the actual body volume
Factors Governing Volume of Distribution
Lipid water partition coeffecient

pKa value of drug and pH of

medium
Degree of plasma protein binding

Affinity for different tissues

Fat : lean body mass ratio

Diseases like CHF, Cirrhosis, etc

Distribution
Clinical implications

1. Drugs with high V in poisoning not easily

removed by hemodialysis

2. CCF, uremia and other conditions can alter V

(by altering distribution of body water, permeability
of membranes, binding proteins or by
accumulation of metabolites that diplace the drug
from binding sites)
Distribution
Redistribution
Eg. Thiopentone Na, diazepam

Highly lipid-sol drugs

Distributed initially to organs with high-blood flow
like brain, heart, kidney, then less vascular muscle,
fat - Drug withdrawn from highly perfused areas

If site of action is in one of the highly perfused

organs --- redistribution causes termination of drug
action
Distribution
Penetration into brain and CSF

- BBB, Blood- CSF barrier

Lipid soluble drugs easy penetration CNS
action
Efflux transporters Pgp, OATP in brain and
choroidal vessels
Inflamn of meninges / brain increased
permeability
Enzymatic BBB (MAO, cholinesterase) in capillary
walls or cells lining them
Distribution
The BBB is deficient at:
Pituitary gland
Pineal body
Area prostrema (CTZ)
Median eminence
Choroid plexus
Distribution
Passage across placenta

Free passage of lipophilic drugs

Efflux transporter Pgp limits foetal exposure
Nonlipid soluble drugs in high conc /
prolonged period incomplete barrier
Some influx transporters also operate at the
placenta
Plasma protein binding
Acidic drugs albumin
Basic drugs 1 acid glycoprotein

Clinical implications
1. High PPB vasc compartment
2. Bound fraction not available for action, temporary
storage
3. High PPB longer acting
4. Poisoning hemodialysis ineffective
5. Plasma conc free and bound drug
6. Displacement interactions eg. salicylates displace
sulfonylureas
7. Hypoalbuminemia
Distribution
Tissue storage
Drugs may accumulate in specific organ by active
transport or get bound to specific tissue
constituents
Unequally distributed
Larger V and longer DOA
Some may exert local toxicity due to high concn
(tetracyclines on bone & teeth, chloroquine on
retina)
- Drugs may also selectively bind to specific
intracellular organelle (tetracycline to mitochondria)
 Tissue Storage
Skeletal Digoxin
Muscle, Heart
Liver Chloroquine
Thyroid Iodine
Retina Chloroquine
Bone & Teeth Tetracyclines
Adipose Thiopentone,
Tissue ether
Biotransformation
Chemical alteration of drug in the body

WHY?
nonpolar to polar (not reabsorbed, excreted)
Hydrophilic mostly excreted unchanged
eg. Streptomycin, neostigmine

Site
- liver, kidney, intestine, lungs, plasma
Biotransformation
What happens?
1. Inactivation most drugs eg ibuprofen, PCM,
lidocaine
2. Active drug to active metabolite
eg. Morphine, diazepam, allopurinol
3. Activation of inactive drug PRODRUGS
- more stable
- better bioavailability or other Phk properties
- less s/e and toxicity
eg. Levodopa, -methyldopa, enalapril
Biotransformation
Biotransformation reactions

I) Nonsynthetic / Phase I /
Functionalisation reactions
II) Synthetic / Phase II / Conjugation
reactions
Biotransformation
Factors affecting drug metabolism
1. Animal species and strain
2. Age and sex
3. Genetic determinants
4. Nutritional status
5. Hypothermia
6. Route and durn of admn
7. Envtal determinants eg. Air pollution, cigarette
smoke
8. Simultaneous admn of other drugs
9. Hepatic / renal diseases
Biotransformation
I) Nonsynthetic reactions
1. Oxidation
2. Reduction
3. Hydrolysis
4. Cyclisation
5. Decyclisation

II) Synthetic reactions (conjugation)

Biotransformation
I) Synthetic reactions
1.Oxidation
Addition of O2 or vely charged radical
Removal of H2 or +ly charged radical
OH-lation, oxygenation at C,N or S atoms
N or O dealkylation
Oxidative deamination
Biotransformation
Initial insertion of O2 into the molecule

interm highly reactive quinone / epoxide /

superoxide (short-lived)

stable compds
Biotransformation
Oxidative reactions

Monooxygenases in liver

Final step involves Cytochrome P450

hemoprotein, NADPH, Cytochrome P450
reductase, O2
(CYP 3A4/5. CYP2D6, CYP2C8/9) eg. PCM,
steroids, ibuprofen
Biotransformation
Certain drugs like ranitidine oxidised at N,P or
S atom by flavin monooxygenases (liver)

Alcohol, aldehyde etc oxidised by

mitochondrial / cytoplasmic enzymes
Biotransformation
2. Reduction
- converse of oxidation
- cytchrome P450 enz work in opp direction
- Aldehydes, quinones, alcohols eg.
Chloramphenicol, warfarin
Biotransformation
3. Hydrolysis
Cleavage of a drug molecule by taking up a
molecule of water
ester + water = acid + alcohol
Amines (amidases), polypeptides
(peptidases), epoxide metabolites of drugs
(epoxide hydrolases)
eg choline esters, procaine, lidocaine, aspirin,
oxytocin
Biotransformation
4. Cyclisation
- straight chain to ring structure
eg proguanil
5. Decyclisation opening p of ring structure
eg barbiturates
Biotransformation
II) Synthetic reactions
Conjugation of the drug / phase I metabolite
with an endogenous substrate

Polar, highly ionised organic acid

Easily excreted in urine / bile

- high energy requirement
Biotransformation
1. Glucuronide conjn
- most important
- UDP glucuronosyl transferases
- compds with OH / COOH groups
eg. aspirin, PCM, morphine, bilirubin,
steroids, thyroxine
- enterohepatic cycling of drug glucuronides
increases DOA eg contraceptives
Biotransformation
2. Acetylation
- from acetyl CoA
- amino / hydrazine residues
- N-acetyl transferases
- isoniazid , PAS
- slow and fast acetylators
Biotransformation
3. Methylation
- amines and phenols
- methionine and cysteine methyl donors
eg adrenaline, histamine

4. Sulfate conjugation
- phenolic compds and steroids
- sulfotransferases (SULTs)
eg steroids, chloramphenicol
Biotransformation
5. Glycine conjugation
- COOH groups (salicylates)
6. Glutathione conjugation
- mercapturate
- highly reactive quinone / epoxide interm

7. Ribonucleoside / nucleotide synthesis

- activation of purine and pyrimidine
antimetabolites used in cancer chemotherapy
Biotransformation
DRUG EXCRETION (diff pathways)

Drug metabolising enzymes

Microsomal Non microsomal

Smooth ER Cytoplasm, mitochondria

Liver, kidney, gut, lungs Liver, other tissues,plasma

Monooxygenases, CYP, UGTs Esterases, amidases,

conjugases
Oxidn, redn, hydrolysis, Some oxid, red, hydro, all
gluuronide conjn conjn except glucuronide
Inducible Noninducible, genetic
polymorphism
Biotransformation
Both microsomal and nonmicrosomal enzymes
deficient in newborn, esp premature

made up in the first few mths (more quickly in

phase I than conjugn)
Amt and kind of enz controlled genetically
Interspecies and interindividual differences seen
(eg. Cats deficient in UDP-glucuronosyl
transferase)
Difference in rate of metabolism individual
variation in response
Biotransformation
Hoffmann elimination
inactivation of drug by spontaneous
molecular rearrangement (without enzymes)
eg. Atracurium
Biotransformation
Inhibition of metabolism (Cyt
P450)

Enz inhibition
- direct effect on enzymes faster
eg allopurinol, erythromycin, MAO inhibitor
Biotransformation
Microsomal enzyme induction
- Drug, insecticides, carcinogens
DNA
increased enz (gluc transferase)
- Anticonvulsants, rifampicin CYP3A
- Rifampicin, phenobarb CYP2D6

Induction peaks in 4-14 days, maintained till

inducing agent given, then returns to original
value over 1-3 weeks
Biotransformation
Consequences of enzyme induction
Decreased intensity or DOA of drugs eg. OCs
Increased intensity of drugs activated by
metabolism
Tolerance (autoinduvtion) eg. rifampicin
Some endogenous agents are metabolised faster eg.
Bilirubin
Ppt acute intermittent porphyria
Intermittent use of inducer interfere with dose of
another regular drug eg. OHDs
interference with chronic toxicity testing in animals
Biotransformation
Possible uses of enzyme induction
1.Cong nonhemolytic jaundice (due to
decreased bilirubin glucuronidation)
phenobarbitone
2. Cushing's syndrome phenytoin (increases
steroid metabolism)
3. Chronic poisonings
4. Liver disease
Biotransformation
First pass metabolism
Metabolism of a drug during its passage from
the site of absorption into the systemic
circulation
Extent differs for diff drugs and determines oral
bioavailability eg GTN, morphine, lignocaine

Site gut wall, Liver (S.L., transdermal,

parenteral)
- skin, lungs
Biotransformation
Drugs with high 1st pass metabolism

Oral dose considerably higher than S.L. or

parenteral
Marked individual variation in oral dose
Oral bioavailability increased in severe liver
disease
Two drugs competing for first pass metabolism
eg chlorpromazine and propranolol
Excretion
Passage out of systemically absorbed drug

1. Urine most important channel

2. Faeces- unabsorbed drug + excreted in bile

(drug-glucuronide by OATP), OCT, Pgp
- steroids by separate non-specific active
transport mech
- enterohepatic cycling eg rifampicin, OCs
- certain drugs directly excreted in colon eg
anthracene purgatives, heavy metals
Excretion
3. Exhaled air gases and volatile liquids (GA,
alcohol)

4. Saliva and sweat minor importance,

lithium, rifampicin, heavy metals

5. Milk most drugs enter by passive diffusion

Excretion
Renal excretion
Net renal excretion = (GF + tubular secretion) tubular
reabsn

GF filtration depends on PPB

- RBF
Tub reabsn passive diffusion lipid solubility
- ionisation
Hydrophilic highly ionised drugs excretion parallels
GFR
eg aminoglycoside antibiotics
Ionisation use in therapeutics
Excretion
Tubular secretion active transport
a) OATP- penicillin, probenecid, uric acid
b) OCT thiazides, furosemide
Interaction competition for transport
eg. penicillin and probenecid
c) P-gp- Quinidine decreases P-gp levels; decreases
clearance of digoxin
Not well-developed in newborns
Renal fn progressive decrease >50 yrs
Renal clearance of most drugs decreases above 75
yrs
Kinetics of elimination
Elimn = inactivn + excretn

Clearance - volume of plasma from which the

drug is completely removed in unit time

CL = rate of elimn (C= plasma conc)

C
Kinetics of elimination
First order or exponential kinetics
Elimn conc ; CL is constant
Constant fraction eliminated

Zero order or linear kinetics

Elimn constant irrespective of concn
Constant amt eliminated eg ethylalcohol

1st order to 0 order eg phenytoin, warfarin

Kinetics of elimination
Plasma half-life (t)
The time taken for the plasma conc of the
drug to be reduced to half its original value

- distribution t
- elimination t
Kinetics of elimination
t = ln2/k
ln2 = natural logarithm of 2 (0.693)
k = elimn rate constant of the drug

k = CL /V

t = 0.693 x V/CL
Kinetics of elimination
Repeated drug administration at short intervals

Accumulation till elimn = absn

(Cpss / steady state plasma concn)
Cpss = dose rate /CL
Dose rate = target Cpss x CL

Orally, dose rate = target Cpss x CL

F
Kinetics of elimination
Plateau principle

Target level strategy

anticonvulsants, antidepressants,
antiarrhythmics
Effects not easily quantifiable
Low safety margin
Those given to prevent an event
Kinetics of elimination
Target level strategy
Aim is to achieve a certain plasma concn which
has been defined to be in the therapeutic
range
Drugs with short t, 6-12hrly administration

Marked fluctuations in plasma conc and target

levels intermittently achieved
eg. penicillin, ampicillin, erythromycin
(therapeutically acceptable)
Kinetics of elimination
For drugs with longer t,

Loading dose - a single or few quickly repeated

doses given in the beginning to attain target
concn rapidly

Loading dose = target Cp x V

F
Kinetics of elimination
Maintenance dose
One that is to be repeated at specified
intervals after the attainment of target Cpss
so as to maintain the same by balancing
elimination
Two-phase dosing
Rapid therapeutic effect
Long term safety
Eg. Chloroquine, digoxin, doxycycline
TDM
Useful in the following situations
a. Low safety margin digoxin, anticonvulsants,
antiarrhythmics
b. Potentially toxic drugs used in renal failure
aminoglycosides
c. Poisoning
d. Failure of response without any apparent reason
antimicrobials
e. Individual variations are large antidepressants,
lithium
f. To check pt compliance- psychopharmacological drugs
TDM
Revised = Previous dose rate x target Cpss
dose rate Measured Cpss

TDM of no value for

a. Drugs whose response is easily measurable
antihypertensives
b. Drugs activated in the body levodopa
c. Hit and run drugs reserpine
d. Drugs with irreversible action OP compds
Prolongation of drug
action
WHY?
1. Freq reduced more convenient
2. Better patient compliance
3. Large fluctuations in plasma concn avoided
4. Drug effect maintained overnight without
disturbing sleep - antiasthma
Prolongation of drug
action
HOW?
I. By prolonging absn from site of administration
A) Oral SR tablets, spansules etc- drug particles
coated with resins, plastic materials or other
subst which temporally disperse releaseof the
active ingredient in git
- CR tablet / capsule semipermeable
membrane control release of drug from the
dosage form
Prolongation of drug
action
B) Parenteral
i. Drug in insoluble form benzathine penicillin,
lente insulin
ii. oily solution (depot preparations) progestins
iii. Pellets
iv. Implants
v. Drug + vasoconstrictor

C) Transdermal drug delivery system

Prolongation of drug
action
II. By increasing PPB sulfadoxine

III. By decreasing rate of metabolism small

chemical modification ethinyl estradiol

IV. By decreasing renal excretion penicillin and

probenecid
Targeted drug delivery
devices
To localise and prolong delivery of the contained
drug to a specific target organ

1. Liposomes
Unilamellar or bilamellar nanovesicles produced
by sonication of lecithin or otther biodegradable
phospholipids
When given iv taken up by RES cells, esp liver
and spleen; and some malignant cells
Liposomal amphotericin B in kala azar and some
serious cases of systemic mycosis
Targeted drug delivery
devices
2. Drug releasing implants
-implant coated with drug --- placed in the
target organ --- slow release --- prolonged
delivery of minute quantities of drug by slow
release
Eg. Progestin-impregnated IUCD protection for
upto 5 years
antithrombotic drug-coated stents to prevent
restenosis