PHARMACOKINETICS

Prof CB Choudhary
Pharmacokinetics
Pharmacokinetics is the study of absorption,
distribution, metabolism & excretion of drugs
(ADME).
Movement of drugs into, within & out of the body.
Site of action

Absorption Tissue stores

DRUG PLASMA

Excretion

Metabolism
Contd...
For a drug to produce its specific response it should be
present in adequate concentrations at the site of
action.
This depends on various factors apart from the dose.
Once the drug is administered, it is absorbed i.e.
enters the blood, is distributed to different parts of the
body, reaches the site of action, is metabolised &
excreted.
 Pharmacokinetic Process EXCRETION
ABSORPTION DISTRIBUTION -- STORAGE

Site of action Storage tissue

Bound Free Free Bound
Drug in
dosage
form CONTENTS

Release Blood Urine

FREE DRUG Bile
Drug in Solution Feces
Metabolites Sweat
Protein Bound saliva

Biotransformation
Pharmacokinetics
All these processes involve passage of the drug
molecules across various barriers.
intestinal epithelium
cell membrane
renal filtering membrane
capillary barrier & so on.
To cross these barriers ,the drug has to cross the cell
membrane, or pass in between the epithelium &
endothelial cells.
The cell membrane/biological membrane made
up of two layers of phospholipids with
intermingled protein molecules.
Pharmacokinetics(contd.)
All lipid soluble substances get dissolved in the cell
membrane & they are readily permeable into the cells.
The junctions between adjacent epithelial or
endothelial cells have pores through which small water
soluble molecules can pass.
Movement of some specific substances regulated by
special carrier proteins.
The passage of drugs across biological
membranes involves processes like
passive( filtration, diffusion) & active transport.
Mechanism of transport of drugs across
biological membrane
1. Passive transport
• Simple diffusion
• Filtration
2. Carrier-mediated transport
• Active transport
• Facilitated diffusion
3. Endocytosis & Exocytosis
1. Passive Transport:
Movement of drug across a membrane without any need
for energy.
 Simple diffusion:
 Passage of lipid soluble/non polar uncharged drugs
through membrane from high concentration to low
concentration
 Commonest ,slow process of drug transport without
carrier and energy.
 Higher the lipid-water partition ratio ,higher the rate of
absorption.
 Higher the concentration, higher the rate of absorption
 Larger is the absorptive surface ,greater the drug flux.
 pH –Acidic drugs are absorbed in acidic media & basic drugs
absorbed in basic media.
 E.g. Morphine, aspirin, sulphonamides
 Simple Diffusion
Polar molecules
(ex. Glucose)

small, non -polar ions

(ex. H+, Na+, K+)
molecules
(ex. O2, CO2)
WATER-SOLUBLE
LIPID-SOLUBLE

LIPID-SOLUBLE
Filtration:
 Means passage of water soluble , polar drugs, ion & some
non-polar molecules of low molecular weight through
pores of the membrane.
 The capillaries of some vascular bed ( e.g. In the kidney)
have larger pores which permit the passage of protein
molecules.
2. Specialized Transport
Facilitated diffusion(Quick process):
Movement of drugs across the membrane
selectively facilitated by carrier protein
without energy along the concentration
gradient until carrier is saturated.
This process shows saturability & selectivity.
 Saturability means when binding site of carrier is
completely saturated, the increase in concentration
gradient will no longer transport the drug.
 Selectivity : selection of drugs with specific chemical

structure by the carrier.

 Ex. Chloramphenicol, Pyrimidine, Vit B12
Active Transport (Very quick process):
 Energy dependent movement of drugs across the
membrane against concentration gradient mediated by
mobile carrier macromolecule.
It has got saturability & selectivity.
E.g. Levodopa, α-methyldopa, 5-fluorouracil
Only drugs related to natural metabolites transported
by this process E.g. Levodopa, iron, sugar & amino
acids
3. Endocytosis and Exocytosis
Endo cytosis:
Engulfment of large molecule by the cell membrane &
release them intra cellularly.
Some proteins are taken up by this process like Pino-
cytosis in amoeba.
 Pino cytosis(Fluid phase endo cytosis)
 Phago cytosis(Adsorption phase endo cytosis)

Exo cytosis:
Responsible for excretion of many substances from cells
e.g. Neurotransmitters stored in nerve endings
 Ion-pair Transport
Highly ionized compounds form a neutral ion pair
complex with endogenous mucin of GIT ,then this
complex penetrates the membrane by simple diffusion.
Eg. Quaternary ammonium compound

Simple Facilitated Active

Diffusion Diffusion Transport
•Slow and commonest •Quick & less common •Ver y quick and least
process for lipid soluble process with
compounds, without
commonest process
saturability & •Takes place against
saturability & selectivity
selectivity
•Drugs move from High
•Same as simple
concentration
concentration to low gradient
concentration diffusion
•Carrier & energy not •Carrier required •Both carrier &
required without energy energy required
 Contd...

Absorption:
 Entry of drug from the site of administration to the circulation
 The rate & degree of absorption can be influenced by various
factors. E.g.
Factors related to the drug:
 Physical state
 Particle size(smaller the particle ,better the absorption)

 Chemical nature

 Excipient or adjuvants present in the drug

 Disintegration time

 Dissolution time

 Specialized preparation of the drug.

Factors related to absorbing medium:
Gut motility
pH of the gut
Presence of food & other drugs in the gut
Vascularity of the area & the site of administration
Factors Influencing Drug Absorption
Disintegration & Dissolution Time:
The drug taken orally should disintegrate to be absorbed.
It then has to dissolve in GIT fluids.
In SC & IM the drug molecule has to dissolve in tissue
fluids.
Liquids are absorbed faster than solids.
Delay in disintegration & dissolution as with poorly water
soluble drugs
(Aspirin) result in delayed absorption.
Formulation:
Pharmaceutical preparations are formulated to produce
desired absorption.
Diluents like starch & lactose used as inert substances
may sometimes interfere with absorption.
Lipid Solubility:
Lipid soluble drugs absorbed faster & better by
dissolving in the phospholipids of cell membrane
Particle Size:
Small particles absorbed better.
Drugs absorbed better when given as small particles:
 E.g. Corticosteroids, Digoxin, Aspirin, Griseofulvin,
Tolbutamide
Particle size of a drug kept large when it has to act on
the gut only. E.g, anthelmintics
pH & ionisation:
Ionised drugs - poorly absorbed.
Unionised drugs - lipid soluble & well absorbed.
Strong electrolytes are almost completely ionised at both
acidic (stomach) & alkaline pH (intestine).
Most drugs are weak electrolytes & exist in both ionised &
unionised forms.
Degree of ionisation depends on the pH of the
medium.
 Acidic drugs remain unionised in the acidic media of
the stomach & are rapidly absorbed from the stomach Eg.
Aspirin, barbiturates
 Weakly acidic drugs forms salts with bases & are

available for use as sodium & potassium salts E.g.

Phenobarbitone sodium, Potassium penicillin V .
 Weakly basic drugs form salts with acids & we have

their Hydrochlorides & sulphates E.g. Ephedrine

Hydrochloride, Atropine sulphate.
Basic drugs are unionised when they reach the
alkaline medium of the intestine from where they are
rapidly absorbed. E.g. Pethidine, Ephedrine
Basic drug given IV may diffuse from blood into the
stomach because of acidic pH &may ionise quickly.
This is known as “ion trapping”.
Strong acids & bases are highly ionised &
therefore poorly absorbed E.g. Heparin,
Streptomycin.
 HENDERSON –HASSELBALCH EQUATION :-
The extent of trapping or the ratio of ionised to unionised
form of a drug depends on the drugs acid dissolution
constant(pKa) & the pH of the environment.
The relationship between the dissolution constant of a drug
(pKa) & the pH of the environment around it & the extent
of its ionisation can be obtained by Henderson
Hasselbach equation.
From this equation, ratio of unionised form of drug to its
ionised form can be obtained.
pKa= pH + log (Concentration of unionised / Concentration of
ionised acid)
When pH= pKa, the drug is 50% ionised & 50% unionised
Acidic drugs have low pKa (2.5-6) whereas basic drugs
have higher pKa( 8-10)
HENDERSON –HASSELBALCH EQUATION :-

pKa =pH + log [HA]/ [A‾] where,

pKa = -ve log of Acidic dissociation constant of the weak electrolyte.
[A-]=Conc. Of Ionized drug.
[HA]=Conc. Of Unionized drug.
If [A-]/ [HA]= 1, since Log 1 =0 then pH =pKa. Thus , pKa is
numerically equal to pH at which the drug is 50%
Ionized.
Contd...
Area & Vascularity of the absorbing surface:
Larger the area of the absorbing substance & more the
vascularity, better is the absorption.
Thus most drugs are absorbed from the small intestine.
GI motility:
Gastric emptying time: If faster , absorption is faster
from intestine.
Intestinal motility when increased as in diarrhoeas, drug
absorption reduced.
Presence of food:
 Delays gastric emptying, dilutes the drug & delays absorption.
 Drug may form complexes with food; such complexes poorly absorbed
e.g. Tetracycline chelate calcium present in food.
 Drugs like Ampicillin, Roxithromycin, Rifampicin are well absorbed
only on empty stomach.

Diseases of the gut like malabsorption & achlorhydria result in

delayed absorption.
 Acidic drugs poorly absorbed in presence of achlorhydria.

Metabolism:
 Nitroglycerine, Insulin may be degraded in the GIT(First Pass
Metabolism)
 Such drugs used by alternative route or in higher doses.
First Pass Metabolism (Presystemic
Metabolism or First Pass Effect)
Metabolism of a drug during its first passage from the
site of absorption to the systemic circulation.
An important feature of oral route of administration.
Drugs given orally may be metabolized in the gut wall
and in the liver before reaching the systemic
circulation.
Extent of first pass metabolism differs from drug to drug
and among individuals from partial to total inactivation
When partial, it can be compensated by giving higher
dose of the drug e.g. Nitroglycerine, Propanolol,
Salbutamol
Drugs undergoing complete first pass metabolism,
route of administration has to be changed. E.g.
Isoprenaline, Hydrocortisone, Insulin
Liver Disease increases bioavailability due to reduction
in hepatic metabolism.
Clinical Significance of First Pass
Metabolism
Reduces bioavailability.
Extent of metabolism depends upon the drug & the
individuals. E.g. Morphine, Chlorpromazine,
Nitroglycerine,Verapamil,Testosterone,Insulin,Lignoca
ine
Measures to compensate first pass effect:
Dose has to be increased for some drugs like Propanolol
Route has to be changed for some others like
Hydrocortisone, Insulin
Absorption from Parenteral Routes
On i.v. administration, drugs directly reach the
circulation.
On i.m. injection, drug molecules should dissolve in
the tissue fluids and then be absorbed.
Absorption fast since muscles have rich blood supply
Lipid soluble drugs absorb faster.
Absorption from s.c. administration slower but rate of
absorption somewhat steady.
Inhaled drugs rapidly absorbed from the pulmonary
epithelium, particularly the lipid soluble ones.
Bioavailability
Fraction of the drug that reaches the systemic
circulation in unchanged form following
administration by any route.
When a drug is given IV, bioavailability is 100%.
On IM , s.c. inj. & sublingual administration, drugs
are almost completely absorbed >75%
On Oral route bioavailability may be low due to
incomplete absorption & first pass metabolism. E.g.
Chlortetracycline 30%, Carbamezipine 70%,
Chloroquine 80%, minocycline & Diazepam almost
100%.
Transdermal preparations are absorbed
systemically ,may have 80-100% bioavailability.
Rectal administration 30-almost 100% .
Large bioavailability variations of a drug can result
in toxicity or therapeutic failure.
Factors Influencing Bioavailability are the same
which influences the absorption of a drug.

Patient related Routes of

Factors administration

BIOAVAILA
BILITY
Determination of Bioavailability

The drug is injected IV & plasma concentration measured at hourly intervals.

Plasma concentration is plotted against time on a graph paper .Similarly plasma
concentration time graph also obtained after oral administration of the same
dose of the drug. The area under the curve (AUC) is measured .
AUC(oral)
Drug Bioav. (%)= ------------- x100
AUC IV
Bioequivalence
Bioequivalence means a comparison of bioavailability of
different formulations of the same drug.
If two or more similar dosage forms of the same drug
reach the blood circulation at the same relative rate & to
the same relative extent, these are called bioequivalent
preparations(brands) of the generic drug.
Two similar dosage forms of one drug entity can be called
bioequivalent if their plasma level profiles are comparable
& superimposable or fall within specific regulated limits.
Differences in bioavailability assume a much greater
concern with drugs that show a steep dose relationship.
E.g. Phenytoin, warfarin & other oral anticoagulants,
digoxin
Distribution
After the drug reaches the systemic circulation, it gets
distributed to the tissue
It should cross several barriers before reaching the side of
action
Distribution also involves the same possess i.e. that is
filtration, diffusion and specialized transport
Various factors determine the rate and extent of
distribution that is lipid solubility, ionization, blood flow
and binding to plasma proteins and cellular proteins
Unionized lipid soluble drug widely distributed through
out the body
 Plasma Protein Binding
Acidic drugs binds with albumin.
Basic drugs binds with α-1 acidic glycoprotein.
There are additionally some special globulins
(transferrins, ceruloplasmin, transportin, thyroxine
binding globulin)
Protein bound drugs pharmacologically inactive, non
diffusible, not metabolised, not excreted
Acts as a temporary storage of the drug
Serves as reservoir,bound portion unavailable for
action,metabolism & excretion.
Drugs bind to plasma proteins reversibly. Dynamic
equilibrium between the free & bound form of drugs.
When the plasma concentration of free drug falls, the
equilibrium is maintained by immediate release of the
drug from protein binding site.
Highly Protein Bound Drugs(>90%):
Phenylbutazone, Diazepam, Propranolol, Doxycycline,
Phenytoin , Digoxide, Tolbutamide
Low Protein Bound Drugs:
Lithium , Ouabain, Ethosuccimide, Antipyrines
Clinical Significance
 Higher the protein binding, longer the duration of action
 Highly protein bound drugs largely restricted to vascular
compartments & have low Vd.
 In hypo proteinaemia, the dose of the highly protein bound
drugs should be properly adjusted
 Drug interactions may occur when 2 drugs have the affinity
for the same binding site.
 Highly protein bound drugs are less effective in acute
conditions & less amenable to dialysis in over dosage.
 Protein binding may delay the drug reaching the site of
action
Blood Brain Barrier
The capillary boundary present between the blood
and the brain is called blood brain barrier(BBB).
In the brain capillaries, the endothelial cells joined by
tight junctions.
Endothelial cells of the brain capillaries lack
intercellular pores, instead have tight junctions.
Glyial cells envelop the capillaries and together they
form BBB.
Lipid soluble and unionized form of drugs can pass
through BBB and reach the brain e.g.
 BBB CONTD...
Barbiturates, diazepam, volatile anaesthetics,
amphetamine etc.
Lipid insoluble & ionised particles donot cross BBB
e.g. Dopamine and amino glycosides.
Pathological states like meningitis and encephalitis
increased the permeability of the BBB. They allow the
normally impermeable substances to enter the brain
e.g. Penecilline G in normal conditions has poor
penetration through BBB but it increases during
meningitis and encephalitis.
 Placental Barrier
Certain drugs administered to the pregnant women
can cross placenta and affect the foetus/new born e.g.
d- tubocurarine and substances with high molecular
weight like insulin cannot cross the placental barrier.
 Volume of Distribution (Vd)
Body can be considered as a single compartment into
which drugs are distributed uniformly(for the purpose of
pharmacokinetic studies)
Vd relates to the amount of drug in the body to the
concentration of drug in the blood or plasma depending
on fluid measured .
Vd also referred to as apparent volume of distribution.
Defined as the fluid volume in which drug appears to be
distributed after equilibrium.
Vd = Amount of drug in the body
Plasma Concentration
Clinical Importance of Vd
 Helpful for determination whether further dose has to be given or
not.
 Drugs having higher Vd have longer half-life.
 Vd plays an important role in drug displacement.
 If 2 drugs bind to the same plasma protein, drug interactions take place.
 E.g. Tolbutamide and Sulfonamide bind to the same plasma protein i.e.
Albumin
So, Sulfonamide displaces Tolbutamide from albumin and Tolbutamide
toxicity can occur.
 The knowledge of Vd of drugs is clinically important in the
treatment of poisoning. Drugs with large Vd(Pethidine) are not
easily removed by Haemodialysis because such drugs are widely
distributed in the body.
Important facts about Vd:
Drugs retained mostly in the plasma----Vd small (E.g.
Aspirin, aminoglycosides).
Drugs distributed widely in the tissues------Vd is large
(Eg. Pethidine)
Drugs extensively bound to plasma proteins have a low
Vd(~3L) E.g. Phenylbutazone
Low Vd drugs (Aminoglycosides) may have a larger Vd in
presence of oedema or ascites due to increased
ECF( Extracellular fluid) volume.
 Biotransformation ( Metabolism )
Process of biochemical alteration of the drug in the
body.
Body treats most drugs as foreign substances
(Xenobiotics) & tries to inactivate & eliminate them by
various biochemical reactions.
These processes converts the drugs into more polar
water soluble compounds so that they are easily
excreted through the kidneys.
Some drugs may be excreted largely unchanged in the
urine. E.g. Frusemide, atenolol
Site: Liver, to a small extent by the Kidneys, gut mucosa,
lungs, blood & skin.
Consequences of Biotransformation
Generally inactivates the drug.
Some drugs may be converted to metabolites which are
also active or more active than the parent drug.
Biotransformation may also activate an inactive drug.
When the metabolite is active, the duration of action
gets prolonged.
Consequences of Biotransformation with Example
Active drug to Active drug to Inactive drug to
inactive active active metabolite
metabolite metabolite (Prodrug)
•Primidone ---
Phenobarbitone • Levodopa ---
•Digitoxin ---- Dopamine
• Lignocaine Digoxin • Prednisone ---
• Chloramphenicol Prednisolone
• Ibuprofen •Diazepam ---- • Enalaril ---
Oxazepam Enalaprilat
• Bacampicillin ---
•Allopurinol --- Ampicillin
Alloxanthine
Active Drug
Metabolism
Active Inactivation Active metabolite Active Drug
Inactive Drug
Metabolite

Biotransformation
Prodrug:
An inactive drug which gets converted into an active form in
the body.
 In some drugs active metabolite may be toxic E.g. Paracetamol
converted to N-acetyl-p-benzoquinoneimine which causes
hepatotoxicity
 Cyclophosphamide converted to Acroline which causes bladder

toxicity.
Some drugs may be converted into epoxides which are short
acting but highly reactive molecules.
 They bind to cells & tissues resulting in toxicity.
 Epoxide induced liver damage is countered to a large extent by

glutathione conjugation.
Enzymes in Biotransformation:
Mainly:
Microsomal Enzymes: Liver microsomes in
the cytoplasm & mitochondria of the liver cells
Non-microsomal Enzymes: in the plasma &

other tissues
Microsomal enzymes are a mixed function oxidase
system or monooxygenases & require Nicotine
adenine dinucleotide phosphate (NADPH) &
Oxygen.
Microsomal enzymes are important in the oxidation
reduction reactions .
1) NADPH cytochrome p450 reductase
2) Hemoprotein, cytochrome P450 (CYP/P450)
Several isoforms of P450 enzymes. 74 CYP gene families

are known.1st is important CYP-1 CYP-2 & CYP-3 groups.

Chemical reactions of Biotransformation takes place in 2
phases:
 Phase I: Nonsynthetic Reactions
 Phase II : Synthetic Reactions
Phase I Reactions:
 Converts the drug to a more polar metabolite by oxidation, reduction or
hydrolysis.
 Oxidation:
 The process of addition of oxygen (or negatively charged radical) to a drug
molecule or removal of hydrogen ( or a positively charged radical from a drug
molecule).
 Most important metabolising reactions mostly catalysed by monooxygenases
present in the liver.
 They are carried by a system which includes Cytochrome p450 , NADPH
& molecular oxygen. There are several types of oxidation reactions:
 Hydroxylation: Salicylic acid----Gentisic acid , Phenytoin—Hydroxy phenytoin
 Dealkylation: Imipramine ------Desmethylimipramine , codeine---morphine
 S-oxidation( Sulphoxide formation) : Cimetidine----Cimetidine sulphoxide
 Deamination: Amphetamine----Benzylmethyl ketone
 Oxidation can also be catalysed by non-microsomal enzymes.E.g Ethyl
alcohol----CO2 + H2O
Phase I Reaction contd...
Reduction:
Catalysed by microsomal or non-microsomal enzymes. Many
types of reduction reactions:
 Nitroreduction: E.g. Chloramphenicol---Arylamine
 Ketoreduction: Cortisone----Hydrocortisone

 Disulfiram & Nitrites are reduced by non microsomal enzymes

Hydrolysis:
Process where a drug molecule is split by addition of molecule
of H2O (Both microsomal or nonmicrosomal enzymes may be
involved)
Esterases, Amidases & peptidases catalyse hydrolytic reactions.
E.g. Acetylcholine + H2O------Choline + Acetic acid
Procaine ,Atropine ,Pethidine & Neostigmine are metabolised
by hydroxylation.
If metabolite of phase I reaction sufficiently
polar, excreted by the kidneys.
If not sufficiently polar to be excreted, it
undergoes phase II reactions.
Phase II Reactions
Endogenous water soluble substances like
Glucuronic acid, sulphuric acid , glutathione or an
amino acid combine with the drug or its phase I
metabolite to form a highly polar conjugate which is
inactive & gets excreted by the kidneys.
Conjugation results invariably the inactivation of the
drug.
Large molecules are excreted by the bile.
Some products of conjugation are Glucuronides,
ethereal sulphates & aminoacid conjugates.
 Glucuronide Conjugation
Most common type of metabolic reaction.
Endogenous substances like bilirubin & steroid
hormones also undergo conjugation.
 The drug or its phase I metabolites undergoes conjugation
with uridine diphosphate glucuronic acid (UDPGA)
followed by transfer of glucuronic acid to the drug.
 Reaction is catalyzed by the enzyme UDP glucuronyl
transferase & the drug-glucuronyl conjugate form is polar,
inactive & can be readily excreted through the kidneys.
Glucuronyl

 Drug+ UDPGA Transferase Drug glucuronide+UDP

Excreted
Glucuronyl transferase inadequately formed in
the neonates. Hence, bilirubin levels increased
resulting in neonatal jaundice.
Grey baby syndrome – an adverse effect of high dose
of chloramphenicol seen in neonates because of lack
of UDP glucuronyl transferase.
Several endogenous substances involved in
conjugation are supplied by the diet. Hence nutrition
is also important for conjugation & thereby
detoxification of drugs.
Acetylation:
 Sulphonamides & isoniazid undergo conjugation with acetyl coA
( acetylation ).
 The reaction is catalysed by N-acetyl transferase found in the
cytoplasm.
Methylation:
 Catecholamines like adrenaline & dopamine undergo methyl
conjugation or methylation catalysed by enzyme transmethylase.
 The methyl group is donated by methionine & cysteine.
Glutathione conjugation:
 Inactivates highly reactive intermediates formed during
metabolism of drugs like paracetamol.
Others are amino acid conjugation, sulphate conjugation &
glycine conjugation.
 Enzyme Induction & Enzyme Inhibition
Microsomal enzymes are located in the microsomes that line
the smooth endoplasmic reticulum of liver cells .
Enzyme induction:
 The synthesis of these microsomal enzymes mainly CytP450
can be enhanced by certain drugs & environmental pollutants
 Speeds up the biotransformation of the inducing drug itself &
other drugs metabolised by the same microsomal enzymes
 e.g. Phenobarbitone , Rifampicin, cigarette smoke, DDT,
Carbamazepine, Phenytoin are some enzyme inducers.
Enzyme induction may be selective for some particular
enzyme ( DDT) or non selective ( Phenobarbitone)
Enzyme induction may be blocked by drugs that inhibit
protein synthesis.
 Clinical Importance of Microsomal Enzyme
Induction
Drug Interactions:
 Therapeutic failure: Enzyme induction may reduce the duration of
action of some other drugs by speeding up metabolism which can
result in therapeutic failure.
 E.g. failure of oral contraceptives in pts taking rifampicin.

 Toxicity: Due to production of higher amount of toxic intermediate

metabolites
 e.g. Pt undergoing treatment under rifampicin likely to develop
hepatotoxicity with paracetamol because a higher amount of toxic
intermediate metabolite of Paracetamol is formed due to Enzyme
induction.

Tolerance to drugs:

Result in Disease:
 Antiepileptics enhance the breakdown of Vit D resulting in osteomalacia
on long term use.

Variable Response:
 Chronic smokers & alcoholics enzyme induction may result in failure to
achieve the expected response to some drugs metabolised by the same
enzymes.

Therapeutic application:
 Neonates deficient in both microsomal & non microsomal enzymes .
 Their capacity to conjugate bilirubin is low which results in jaundice.
 Administration of Phenobarbitone helps in rapid clearance of jaundice in
the neonates by enhancing bilirubin conjugation.
 Enzyme Inhibition
Some drugs inhibit cytP450 enzyme activity.
Drugs like cimetidine & ketoconazole bind to cytP450 & thus
competitively inhibit the metabolism of endogenous
substances like testosterone & other drugs given
concurrently.
Enzyme inhibition by the drugs is the basis of several drugs
interaction.
Chloramphenicol, erythromycin, ketoconazole,
cimetidine ,ciprofloxacin are some enzyme inhibitors.
With some drugs, binding of enzymes may be
irreversible leading to inactivation of the enzyme. Such
substrates are called suicide inhibitors. E.g. Selegiline,
 Factors influencing Biotransformation
Genetic Variation results in altered metabolism of
drugs.
E.g. Succinylcholine metabolised very slowly in people
with defective pseudocholine esterase resulting in
prolonged apnoea.
Environmental Pollutants like Cigarette smoke cause
enzyme induction.
Age At extremes of age, the activity of metabolic
enzymes in the liver are low.Hence there is increased
risk of toxicity with drugs.
Diseases of the Liver
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