Pharmacokinetics

Dr. D. BY
K. Brahma
Department of Pharmacology
DR. JOSEPH, OYEPATA SIMEON
NEIGRIHMS, Shillong
What is Pharmacokinetics
 how the human body act on the drugs?

 Pharmacokinetics is the quantitative study of drug movement

in, through and out of the body. Intensity of effect is related to
concentration of the drug at the site of action, which depends
on its pharmacokinetic properties

 Pharmacokinetic properties of particular drug is important to

determine the route of administration, dose, onset of action,
peak action time, duration of action and frequency of dosing
Relationship – Dynamics and
Kinetics
Dosage Regimen
Absorpti
on
Pharmacokineti Distributi
cs on
Metaboli
Concentration
sm in
Excretio
Plasma
Pharmacodynam n

ics
Concentration at the
site of action

Effect
The Pharmacokinetic Process
The Pharmacokinetic Process
Biological Membrane - image
Drug Transportation
 Drug molecules can cross cell membrane
by:
 Passive Diffusion
 Protein – mediated transport (carrier mediated)
 Facilitated Transport
 Active trnsport
 Primary
 Secondary
Passive transport (down hill
movement)
 Most important Mechanism for most of the Drugs
 Majority of drugs diffuses across the membrane in the
direction of concentration gradient
 No active role of the membrane
 Proportional to lipid : water partition coefficient
 Lipid soluble drugs diffuse by dissolving in the lipoidal matrix
of the membrane
 Characteristics
 Not requiring energy
 Having no saturation
 Having no carriers
 Not resisting competitive inhibition
Passive transport
Affecting factors :
the size of molecule
lipid solubility
polarity
degree of ionization
the PH of the environment
such as: fluid of body
fluid in cell
blood, urine
Remember
 The drugs which are Unionized, low polarity
and higher lipid solubility are easy to
permeate membrane.
 The drugs which are ionized, high polarity
and lower lipid solubility are difficult to
permeate membrane.
pH Effect
 Most of drugs are weak acids or weak
bases.
 The ionization of drugs may markedly
reduce their ability to permeate
membranes.
 The degree of ionization of drugs is
determined by the surrounding pH and their
pKa.
Henderson–Hasselbalch Equation

pKa = negative logarithm of acid dissociation constant

[A-] = ionized Drug

[HA] = unionized drug

pH Vs ionization
Implications
 Acidic drugs re absorbed are largely unionized in
stomach and absorbed faster while basic drugs
are absorbed faster in intestines
 Ion trapping
 Acidic drugs are excreted faster in alkaline urine –
urinary alkalizers
 Basic drugs are excreted faster in acidic urine –
urinary acidifiers
Filtration
 Passage of Drugs through aqueous pores in
membrane or through Para cellular space
 Lipid insoluble drugs can cross – if the molecular
size is small
 Majority of intestinal mucosa and RBCs have
small pores and drugs cannot cross
 But, capillaries have large paracellular space and
most drugs can filter through this
Filtration
Carrier Mediated Transport
 Involve specific membrane transport proteins know as drug
transporters or carriers – specific for the substrate

 Drug molecules bind to the transporter, translocated across

the membrane, and then released on the on other side of the
membrane.

 Specific, saturable and inhibitable

 Depending on Energy requirement - Can be either Facilitated

(passive) or Active Transport
Facilitative transporters
 Move substrate of a
single class
(uniporters) down a
concentration gradient

 No energy dependent
 Similar to entry of
glucose into muscle
(GLUT 4)
Active Transport –
energy dependent
 Active (concentrative) transporters
 can move solutes against a concentration gradient
 energy dependent
 Primary active transporters - generate energy
themselves (e.g. ATP hydrolysis)

 Secondary transporters - utilize energy stored in

voltage and ion gradients generated by a primary
active transporter (e.g. Na+/K+-ATPase)
 Symporters (Co-transporters)
 Antiporters (Exchangers)
Major Drug Transporters
• ATP-Binding Cassette Transporters (ABC) Super
family – Primary active transport
• P-glycoprotein (P-gp encoded by MDR1)
• Intestinal mucosa, renal tubules and blood brain barrier etc.
• Mediate only efflux of solute from cytoplasm - detoxification
 Solute Carrier (SLC) transporters – Secondary
active transport
 Organic anion transporting polypeptides (OATPs)
 Organic cation transporters (OCTs)
 Expressed in liver and renal tubules – metabolism and
excretion of drugs
Pinocytosis
 It involves the invagination of a part of the
cell membrane and trapping within the cell
of a small vesicle containing extra cellular
constituents. The vesicle contents can than
be released within the cell, or extruded from
the other side of the cell. Pinocytosis is
important for the transport of some
macromolecules (e.g. insulin through BBB).
 1. Absorption of Drugs
 Absorption is the transfer of
a drug from its site of
administration to the blood
stream
 Most of drugs are absorbed
by the way of passive transport
 Intravenous administration
has no absorption
 Fraction of administered
dose and rate of absorption are
important
Factors affecting absorption
Drug properties:
lipid solubility, molecular weight, and polarity etc
 Blood flow to the absorption site
 Total surface area available for absorption
 Contact time at the absorption surface
 Affinity with special tissue
Routes of Administration (important):
Factors affecting absorption – contd.
Route of administration:
 Topical:
 Depends on lipid solubility – only lipid soluble drugs are
penetrate intact skin – only few drugs are used
therapeutically
 Examples – GTN, Hyoscine, Fentanyl, Nicotine,
testosterone and estradiol
 Organophosphorous compounds – systemic toxicity
 Abraded skin: tannic acid – hepatic necrosis
 Cornea permeable to lipid soluble drugs
 Mucus membranes of mouth, rectum, vagina etc, are
permeable to lipophillic drugs
Factors affecting absorption – contd.
Route of administration:
 Subcutaneous and Intramuscular:
 Drugs directly reach the vicinity of capillaries –
passes capillary endothelium and reach
circulation
 Passes through the large paracellular pores
 Faster and more predictable than oral absorption
 Exercise and heat – increase absorption
 Adrenaline – decrease absorption
Factors affecting absorption – contd.
Route of administration: Oral Route
 Physical properties – Physical state, lipid or water
solubility
 Dosage forms:
 Particle size
 Disintegration time and Dissolution Rate
 Formulation – Biopharmaceutics
 Physiological factors:
 Ionization, pH effect
 Presence of Food
 Presence of Other agents
Oral Administration – 1st pass
metabolism
 Before the drug reaches
the systemic circulation,
the drug can be
metabolized in the liver
or intestine. As a Result,
the concentration of
drug in the systemic
circulation will be
reduced.
1st pass Elimination – Metabolism in
liver
Buccal cavity
Stomach

Vena
Intestine cava
Portal
vein

Rectum
Buccal and Rectal – bypasses liver

Vena
cava
Absorption – contd.
 Intravenous administration has no
absorption phase
 According to the rate of absorption:
Inhalation→Sublingual→Rectal→intramusc
ular→subcutaneous→oral→transdermal
Example – Nitroglycerine:
IV effect – immediate, SL – 1 to 3 min and
per rectal – 40 to 60 minute
Bioavailability
 Bioavailability refers to the rate and extent of absorption of
a drug from dosage form as determined by its
concentration-time curve in blood or by its excretion in
urine. It is a measure of the fraction (F) of administered
dose of a drug that reaches the systemic circulation in the
unchanged form
 Bioavailability of drug injected i.v. is 100%, but is frequently
lower after oral ingestion, because:
 The drug may be incompletely absorbed
 The absorbed drug may undergo first pass metabolism in
intestinal wall and/or liver or be excreted in bile.
 Bioequivalent
 Practical Significance – low safety margin drugs
Biovailability - AUC
AUC – area under the
curve AUC p.o.
Plasma concentration (mcg/ml)

F = ------------ x 100%
F – bioavailability AUC i.v.

0 5 Time (h) 10 15
Biovailability – contd.

MTC

MEC
2. Distribution of Drugs
 It is the passage of drug from the circulation to the
tissue and site of its action.
 The extent of distribution of drug depends on its
lipid solubility, ionization at physiological pH
(dependent on pKa), extent of binding to plasma
and tissue proteins and differences in regional
blood flow, disease like CHF, uremia, cirrhosis
 Movement of drug - until equilibration between
unbound drug in plasma and tissue fluids
Volume of Distribution (V)
 Definition: Apparent Volume of distribution is defined as
the volume that would accommodate all the drugs in the
body, if the concentration was the same as in plasma
 Expressed as: in Liters

Dose administered IV
V=
Plasma concentration
Volume of Distribution (V)

Total Body Fluid = 42 L (approx.)

Volume of Distribution (V)
 Chloroquin – 13000 liters, Digoxin – 420 L,
Morphine – 250 L and Propranolol – 280 L
 Streptomycin and Gentamicin – 18 L
(WHY ?)

`Vd` is an imaginary Volume of Fluid which will accommodate the entire

quantity of the drug in the body, if the concentration throughout
this imaginary volume were same as that in plasma
Volume of Distribution (V)
Vd = IV dose/C
Factors influencing Vd
 Lipid solubility (lipid : water partition
coefficient)
 pKa of the drug
 Affinity for different tissues
 Blood flow – Brain Vs Fat
 Disease states
 Plasma protein Binding
Redistribution
 Highly lipid soluble drugs – distribute to brain, heart and kidney etc.
immediately followed by muscle and Fats
Brain and CSF Penetration
Blood brain barrier (BBB): includes the capillary endothelial cells (which
have tight junctions and lack large intracellular pores) and an investment of
glial tissue, over the capillaries. A similar barrier is loctated in the choroid
plexus
Brain and CSF Penetration – contd.
 BBB is lipoidal and limits the entry of non-lipid soluble drugs
(amikacin, gentamicin, neostigmine etc.).
(Only lipid soluble unionized drugs penetrate and have action on
the CNS)
 Efflux carriers like P-gp (glycoprotein) present in brain
capillary endothelial cell (also in intestinal mucosal, renal
tubular, hepatic canicular, placental and testicular cells)
extrude drugs that enter brain by other processes.
(Inflammation of meanings of brain increases permeability of
BBB)
 Dopamine (DA) does not enter brain, but its precursor
levodopa does. This is used latter in parkinsonism.
Placental Transfer
 Only lipid soluble Drugs can penetrate –
limitation of hydrophillic drugs
 Placental P-gp serves as limiting factor
 But, REMEMBER, its an incomplete
barrier – some influx transporters operate
 Thalidomide
Plasma Protein Binding
 Plasma protein binding (PPB): Most drugs possess
physicochemical affinity for plasma proteins. Acidic
drugs bind to plasma albumin and basic drugs to
α1-glycoprotein
 Extent of binding depends on the individual compound.
Increasing concentration of drug can progressively
saturate the binding sites
The clinical significant implications of PPB are:
a) Highly PPB drugs are largely restricted to the vascular
compartment and tend to have lower Vd.
b) The PPB fraction is not available for action.
c) There is an equilibration between PPB fraction of drug
and free molecules of drug.
Plasma Protein Binding – contd.
d) The drugs with high physicochemical affinity for plasma
proteins (e.g. aspirin, sulfonamides, chloramphenicol) can
replace the other drugs(e.g. acenocoumarol, warfarin) or
endogenous compounds (bilirubin) with lower affinity.
e) High degree of protein binding makes the drug long acting,
because bound fraction is not available for metabolism,
unless it is actively excreted by liver or kidney tubules.
f) Generally expressed plasma concentrations of the drug refer
to bound as well as free drug.
g) In hypoalbuminemia, binding may be reduced and high
concentration of free drug may be attained (e.g. phenytoin).
Tissue storage
Drugs may also accumulate in specific organs or get bound to
specific tissue constituents, e.g.:
 Heart and skeletal muscles – digoxin (to muscle proteins)
 Liver – chloroquine, tetracyclines, digoxin
 Kidney – digoxin, chloroquine
 Thyroid gland – iodine
 Brain – chlorpromazine, isoniazid, acetazolamide
 Retina – chloroquine (to nucleoproteins)
 Iris – ephedrine, atropine (to melanin)
 Bones and teeth – tetracyclines, heavy metals (to
mucopolysaccharide of connective tissue)
 Adipose tissues – thiopental, ether, minocycline, DDT
3. Biotransformation
Metabolism of Drugs
What is Biotransformation?
 Chemical alteration of the drug in the body
 Aim: to convert non-polar lipid soluble compounds
to polar lipid insoluble compounds to avoid
reabsorption in renal tubules
 Most hydrophilic drugs are less biotransformed
and excreted unchanged – streptomycin,
neostigmine and pancuronium etc.
 Biotransformation is required for protection of
body from toxic metabolites
Results of Biotransformation
1. Active drug and its metabolite to inactive metabolites –
most drugs (ibuprofen, paracetamol, chlormphenicol etc.)
2. Active drug to active product (phenacetin – acetminophen
or paracetamol, morphine to Morphine-6-glucoronide,
digitoxin to digoxin etc.)
3. Inactive drug to active/enhanced activity (prodrug) –
levodopa - carbidopa, prednisone – prednisolone and
enlpril – enlprilat)
4. No toxic or less toxic drug to toxic metabolites (Isonizide to
Acetyl isoniazide)
(Mutagenicity, teratogenicity, carcinogenicity, hepatotoxicity)
 Biotransformation - Classification
2 (two) Phases of
Biotransformation:

• Phase I or Non-synthetic –
metabolite may be active or
inactive

• Phase II or Synthetic –
metabolites are inactive
(Morphine – M-6 glucoronide is
exception)
Phase I - Oxidation
 Most important drug metabolizing reaction –
addition of oxygen or (–ve) charged radical or
removal of hydrogen or (+ve) charged radical
 Various oxidation reactions are – oxygenation or
hydroxylation of C-, N- or S-atoms; N or 0-
dealkylation
 Examples – Barbiturates, phenothiazines,
paracetamol and steroids
Phase I - Oxidation
 Involve – cytochrome P-450 monooxygenases (CYP), NADPH and Oxygen
 More than 100 cytochrome P-450 isoenzymes are identified and grouped
into more than 20 families – 1, 2 and 3 …
 Sub-families are identified as A, B, and C etc.
 In human - only 3 isoenzyme families important – CYP1, CYP2 and CYP3

 CYP 3A4/5 carry out biotransformation of largest number (30–50%) of

drugs. In addition to liver, this isoforms are expressed in intestine
(responsible for first pass metabolism at this site) and kidney too

 Inhibition of CYP 3A4 by erythromycin, clarithromycin, ketoconzole,

itraconazole, verapamil, diltiazem and a constituent of grape fruit juice is
responsible for unwanted interaction with terfenadine and astemizole
 Rifampicin, phenytoin, carbmazepine, phenobarbital are inducers of the
CYP 3A4
Oxidation - CYP
CYP3A4/5
Nonmicrosomal Enzyme Oxidation
 Some Drugs are oxidized by non-
microsomal enzymes (mitochondrial and
cytoplsmic) – Alcohol, Adrenaline,
Mercaptopurine
 Alcohol – Dehydrogenase
 Adrenaline – MAO and COMT
 Mercaptopurine – Xanthine oxidase
Phase I - Reduction
 This reaction is conversed of oxidation and
involves CYP 450 enzymes working in the
opposite direction.
 Examples - Chloramphenicol, levodopa,
halothane and warfarin

DOPA-decarboxylase
Levodopa (DOPA) Dopamine
Phase I - Hydrolysis
 This is cleavage of drug molecule by taking up of a molecule of
water. Similarly amides and polypeptides are hydrolyzed by
amidase and peptidases. Hydrolysis occurs in liver, intestines,
plasma and other tissues.
 Examples - Choline esters, procaine, lidocaine, pethidine, oxytocin
Esterase
Ester + H20 Acid + Alcohol
Phase I – contd.
 Cyclization: is formation of ring structure
from a straight chain compound, e.g.
proguanil.
 Decyclization: is opening up of ring
structure of the cyclic molecule, e.g.
phenytoin, barbiturates
Phase II metabolism
 Conjugation of the drug or its phase I metabolite with an endogenous
substrate - polar highly ionized organic acid to be excreted in urine or bile -
high energy requirements

Glucoronide conjugation - most important synthetic reaction

 Compounds with hydroxyl or carboxylic acid group are easily conjugated
with glucoronic acid - derived from glucose

 Examples: Chloramphenicol, aspirin, morphine, metroniazole, bilirubin,

thyroxine

 Drug glucuronides, excreted in bile, can be hydrolyzed in the gut by

bacteria, producing beta-glucoronidase - liberated drug is reabsorbed and
undergoes the same fate - enterohepatic recirculation (e.g.
chloramphenicol, phenolphthalein, oral contraceptives) and prolongs their
action
Phase II metabolism – contd.
 Acetylation: Compounds having amino or
hydrazine residues are conjugated with the help
of acetyl CoA, e.g.sulfonamides, isoniazid
Genetic polymorphism (slow and fast acetylators)
 Sulfate conjugation: The phenolic compounds
and steroids are sulfated by sulfokinases, e.g.
chloramphenicol, adrenal and sex steroids
Phase II metabolism – contd.
 Methylation: The amines and phenols can be
methylated. Methionine and cysteine act as
methyl donors.
 Examples: adrenaline, histamine, nicotinic
acid.
 Ribonucleoside/nucleotide synthesis:
activation of many purine and pyrimidine
antimetabolites used in cancer chemotherapy
Factors affecting Biotransformation
 Factors affecting biotransformation
 Concurrent use of drugs: Induction and inhibition
 Genetic polymorphism
 Pollutant exposure from environment or industry
 Pathological status
 Age
Enzyme Inhibition
 One drug can inhibit metabolism of other – if
utilizes same enzyme
 However not common because different drugs
are substrate of different CYPs
 A drug may inhibit one isoenzyme while being
substrate of other isoenzyme – quinidine
 Some enzyme inhibitors – Omeprazole,
metronidazole, isoniazide, ciprofloxacin and
sulfonamides
Microsomal Enzyme Induction
 CYP3A – antiepileptic agents - Phenobarbitone,
Rifampicin and glucocorticoide
 CYP2E1 - isoniazid, acetone, chronic use of alcohol
 Other inducers – cigarette smoking, charcoal broiled
meat, industrial pollutants – CYP1A
 Consequences of Induction:
 Decreased intensity – Failure of OCPs
 Increased intensity – Paracetamol poisoning (NABQI)
 Tolerance – Carbmazepine
 Some endogenous substrates are metabolized faster – steroids,
bilirubin
4. Excretion
Organs of Excretion
 Excretion is a transport procedure which the
prototype drug (or parent drug) or other
metabolic products are excreted through
excretion organ or secretion organ
 Hydrophilic compounds can be easily excreted.
 Routes of drug excretion
 Kidney
 Biliary excretion
 Sweat and saliva
 Milk
 Pulmonary
 Bile duct
Hepatic Excretion
 Drugs can be excreted in Intesti Portal
bile, especially when the are nes vein
conjugated with – glucuronic
Acid

• Drug is absorbed → glucuronidated or sulfatated

in the liver and secreted through the bile →
glucuronic acid/sulfate is cleaved off by bacteria
in GI tract → drug is reabsorbed (steroid
hormones, rifampicin, amoxycillin, contraceptives)
• Anthraquinone, heavy metals – directly excreted
in colon
Renal Excretion
 Glomerular Filtration
 Tubular Reabsorption
 Tubular Secretion
Glomerular Filtration
 Normal GFR – 120 ml/min
 Glomerular capillaries have pores larger than usual
 The kidney is responsible for excreting of all water
soluble substances
 All nonprotein bound drugs (lipid soluble or insoluble)
presented to the glomerulus are filtered
 Glomerular filtration of drugs depends on their plasma
protein binding and renal blood flow - Protein bound
drugs are not filtered !
 Renal failure and aged persons
Tubular Re-absorption
 Back diffusion of Drugs (99%) – lipid soluble drugs
 Depends on pH of urine, ionization etc.
 Lipid insoluble ionized drugs excreted as it is – aminoglycoside
(amikacin, gentamicin, tobramycin)
 Changes in urinary pH can change the excretion pattern of drugs
 Weak bases ionize more and are less reabsorbed in acidic
urine.
 Weak acids ionized more and are less reabsorbed in alkaline
urine
 Utilized clinically in salicylate and barbiturate poisoning – alkanized
urine (Drugs with pKa: 5 – 8)
 Acidified urine – atropine and morphine etc.
Tubular Secretion
 Energy dependent active transport – reduces the free
concentration of drugs – further, more drug dissociation
from plasma binding – again more secretion (protein
binding is facilitatory for excretion for some drugs)
 OATP – organic acid transport
 OCT – organic base transport
 P-gp
 Bidirectional transport – Blood Vs tubular fluid
 Utilized clinically – penicillin Vs probenecid, probenecid
Vs uric acid (salicylate)
• Quinidine decreases renal and biliary clearance of
digoxin by inhibiting efflux carrier P-gp
Renal Excretion
 Acidic urine
 alkaline drugs eliminated
 acid drugs reabsorbed
 Alkaline urine
- acid drugs eliminated
- alkaline drugs absorbed
Kinetics of Elimination
 Pharmacokinetics - F, V and CL
 Clearance: The clearance (CL) of a drug is the
theoretical volume of plasma from which drug is
completely removed in unit time
CL = Rate of elimination (RoE)/C
Example = If a drug has 20 mcg/ml and RoE is 100
mcg/min
CL = 100/20 = 5 ml /min
Kinetics of Elimination
 First Order Kinetics (exponential): Rate of
elimination is directly proportional to drug
concentration, CL remaining constant
 Constant fraction of drug is eliminated per unit time
 Zero Order kinetics (linear): The rate of
elimination remains constant irrespective of drug
concentration
 CL decreases with increase in concentration
 Alcohol, theophyline, tolbutmide etc.
 Kinetics of Elimination
Zero Order 1st Order
conc.

Time
 CL = RoE/C

Plasma half-life V = dose IV/C

 Defined as time taken for its plasma concentration to be

reduced to half of its original value – 2 phases rapid
declining and slow declining

t1/2 = In2/k
In2 = natural logarithm of 2 (0.693)
k = elimination rate constant = CL / V
t1/2 = 0.693 x V / CL
Plasma half-life
50 + 25 + 12.5 +
1 half-life …………. 50% 6.25 = 93.75

2 half-lives………… 25% 93.75 + 3.125 +

1.56 = 98%
3 half-lives …….…..12.5%
after 5 HL
4 half-lives ………… 6.25%
Excretion - The Platue Principle
Repeated dosing:
• When constant dose of
a drug is repeated before
the expiry of 4 half-life –
peak concentration is
achieved after certain
interval
• Balances between dose
administered and dose
interval
 CL = Roe/C
Repeated Dosing
 At steady state, elimination = input
Cpss = dose rate/CL
Dose Rate = target Cpss x CL
In oral administration
Dose rate = target Cpss x CL/F
In zero order kinetics: follow Michaelis Menten
kinetics
RoE = (Vmax) (C) / Km + C
Vmax = max. rate of drug elimination, Km = Plasma
conc. In which elimination rate is half maximal
Target Level Strategy
 Low safety margin drugs (anticonvulsants, antidepressants,
Lithium, Theophylline etc. – maintained at certain
concentration within therapeutic range
 Drugs with short half-life (2-3 Hrs) – drugs are administered
at conventional intervals (6-12 Hrs) – fluctuations are
therapeutically acceptable
 Long acting drugs:
 Loading dose: Single dose or repeated dose in quick
succession – to attain target conc. Quickly
 Loading dose = target Cp X V/F
 Maintenance dose: dose to be repeated at specific intervals
Monitoring of Plasma concentration
 Useful in
 Narrow safety margin drugs – digoxin, anticonvulsants,
antiarrhythmics and aminoglycosides etc
 Large individual variation – lithium and antidepressants
 Renal failure cases
 Poisoning cases
 Not useful in
 Response mesurable drugs – antihypertensives, diuretics etc
 Drugs activated in body – levodopa
 Hit and run drugs – Reseprpine, MAO inhibitors
 Irreversible action drugs – Orgnophosphorous compounds
Summary – Must Know
 Definition of Pharmacokinetics
 Transport of Drugs across Biological Membrane – different
processes with example
 Factors affecting absorption of drugs
 Concept of Bioavailability
 Distribution of Drugs – Vd and its concept
 Biotransformation Mechanisms with examples
 Enzyme induction and inhibition concept and important examples
 Routes of excretion of drugs
 Orders of Kinetics
 Definition and concept of drug clearance
 Definition of half life and platue principle
Prolongation of Drug action
 By prolonging absorption from the site of
action – Oral and parenteral
 By increasing plasma protein binding
 By retarding rate of metabolism
 By retarding renal excretion