Drug Metabolism

Presented By
Prasanna Kumar Desu M.Pharm., (Ph.D)
Assistant Professor
Department of Pharmaceutics
Vishnu Institute of Pharmaceutical Education & Research
Narsapur, Medak(dt).
 METABOLISM OR BIOTRANSFORMATION
 The conversion from one chemical form of a substance to another.

 The term metabolism is commonly used probably because products of drug

transformation are called metabolites.

 Metabolism is an essential pharmacokinetic process, which renders lipid soluble and

non-polar compounds to water soluble and polar compounds so that they are excreted
by various processes.
 This is because only water-soluble substances undergo excretion, whereas lipid
soluble substances are passively reabsorbed from renal or extra renal excretory sites
into the blood by virtue of their lipophilicity.

 Metabolism is a necessary biological process that limits the life of a substance in the
body.

 Biotransformation: It is a specific term used for chemical transformation of

xenobiotics in the body/living organism.
•a series of enzyme-catalyzed processes—that alters the physiochemical properties of
foreign chemicals (drug/xenobiotics) from those that favor absorption across biological
membranes (lipophilicity) to those favoring elimination in urine or bile (hydrophilicity )
Metabolism : It is a general term used for chemical
transformation of xenobiotics and endogenous
nutrients (e.g., proteins, carbohydrates and fats) within
or outside the body.

Xenobiotics : These are all chemical substances that

are not nutrient for body (foreign to body) and which
enter the body through ingestion, inhalation or dermal
exposure.

They include :
drugs, industrial chemicals, pesticides, pollutants,
plant and animal toxins, etc.
 Functions of Biotransformation

It causes conversion of an

active drug to inactive or
less active metabolite(s)
called as pharmacological
inactivation.

It causes conversion of an

active to more active
metabolite(s) called as
bioactivation or
toxicological activation.

• It causes conversion of an
inactive to more active
toxic metabolite(s) called
as lethal synthesis
 Functions of Biotransformation….contd

• It causes conversion of an
inactive drug (pro-drug) to
active metabolite(s) called
as pharmacological
activation
• It causes conversion of an
active drug to equally active
metabolite(s) (no change in
pharmacological activity)
• It causes conversion of an
active drug to active
metabolite(s) having
entirely different
pharmacological activity
(change in pharmacological
activity)
 Site/Organs of drug metabolism
The major site of drug metabolism is the liver
(microsomal enzyme systems of hepatocytes)
Secondary organs of biotransformation
• kidney (proximal tubule)
• lungs (type II cells)
• testes (Sertoli cells)
• skin (epithelial cells); plasma. nervous tissue
(brain); intestines
Drug Metabolising Enzymes

A number of enzymes in animals are capable of metabolising

drugs. These enzymes are located mainly in the liver, but may
also be present in other organs like lungs, kidneys, intestine,
brain, plasma, etc.

Majority of drugs are acted upon by relatively non-specific

enzymes, which are directed to types of molecules rather than
to specific drugs.

The drug metabolising enzymes can be broadly divided into two

groups: microsomal and non-microsomal enzymes.
Microsomal enzymes: The endoplasmic reticulum (especially
smooth endoplasmic reticulum) of liver and other tissues
contain a large variety of enzymes, together called microsomal
enzymes

(microsomes are minute spherical vesicles derived from

endoplasmic reticulum after disruption of cells by
centrifugation, enzymes present in microsomes are called
microsomal enzymes).

They catalyse glucuronide conjugation, most oxidative

reactions, and some reductive and hydrolytic reactions.

The monooxygenases, glucuronyl transferase, etc are

important microsomal enzymes.
 Non-microsomal enzymes: Enzymes occurring in
organelles/sites other than endoplasmic reticulum
(microsomes) are called non-microsomal enzymes.

These are usually present in the cytoplasm, mitochondria, etc.

and occur mainly in the liver, Gl tract, plasma and other tissues.

They are usually non-specific enzymes that catalyse few

oxidative reactions, a number of reductive and hydrolytic
reactions, and all conjugative reactions other than
glucuronidation.

None of the non-microsomal enzymes involved in drug

biotransformation is known to be inducible.
 Drug Metabolism

Extrahepatic microsomal enzymes

(oxidation, conjugation)

Hepatic microsomal enzymes

(oxidation, conjugation)

Hepatic non-microsomal enzymes

(acetylation, sulfation,GSH,
alcohol/aldehyde dehydrogenase,
hydrolysis, ox/red)
DRUG METABOLISM
 PHASE I BIOTRANSFORMATION

Oxidation

• Oxidation by cytochrome P450 isozymes (microsomal mixed-

functionoxidases).
• Oxidation by enzymes other than cytochrome P450s—most of these
• (a) oxidation of alcohol by alcohol dehydrogenase,
• (b) oxidation of aldehyde by aldehyde dehydrogenase,
• (c) N-dealkylation by monoamineoxidase.
Phase I Reactions
Oxidation :
•Oxidative reactions are most important metabolic reactions, as
energy in animals is derived by oxidative combustion of organic
molecules containing carbon and hydrogen atoms.

•The oxidative reactions are important for drugs because they

increase hydrophilicity of drugs by introducing polar functional
groups such as -OH.

•Oxidation of drugs is non-specifically catalysed by a number of

enzymes located primarily in the microsomes. Some of the
oxidation reactions are also catalysed by non-microsomal enzymes
(e.g., aldehyde dehydrogenase, xanthine oxidase and monoamine
oxidase).
The most important group of oxidative enzymes are microsomal
monooxygcnases or mixed function oxidases (MFO).

These enzymes are located mainly in the hepatic endoplasmic

reticulum and require both molecular oxygen (02) and reducing
NADPH to effect the chemical reaction.

Mixed function oxidase name was proposed in order to

characterise the mixed function of the oxygen molecule, which is
essentially required by a number of enzymes located in the
microsomes.
The term monooxygenses for the enzymes was proposed as they
incorporate only one atom of molecular oxygen into the organic substrate
with concomitant reduction of the second oxygen atom to water.

The overall stoichiometry of the reaction involving the substrate RH which

yields the product ROH, is given by the following reaction:
MFO
RH+02+NADPH+H+ ----------------► R0H+H20+NADP+
The most important component of mixed function oxidases is the
cytochrome P-450 because it binds to the substrate and activates oxygen.

The wide distribution of cytochrome P-450 containing MFOs in varying

organs makes it the most important group of enzymes involved in the
biotransformation of drugs.
ROLE OF CYTOCHROME P450 MONOOXYGENASES
IN OXIDATIVE BIOTRANSFORMATIONS
 The CYP enzymes are heme proteins.
 The heme portion is an iron-containing porphyrin called
protoporphyrin IX, and the protein portion is called the
apoprotein.
 CYP is found in high concentrations in the liver, the major
organ involved in the metabolism of xenobiotics.
 The presence of this enzyme in many other tissues (e.g.,
lung, kidney, intestine, skin, placenta, adrenal cortex) shows
that these tissues have drug-oxidizing capability too.
 The CYP monooxygenases are located in the endoplasmic
reticulum.
 Many of the Cytochrome enzymes that are responsible for
the biosynthesis of steroidal hormones and metabolism of
certain vitamins.
Role Of Cytochrome P450 Monooxygenases In
Oxidative Biotransformation
Participation of the CYP Enzymes in Metabolism of Some
Clinically Important Drugs

CYP Enzyme Examples of substrates

1A1 Caffeine, Testosterone, R-Warfarin
1A2 Acetaminophen, Caffeine, Phenacetin, R-Warfarin
2A6 17 -Estradiol, Testosterone
2B6 Cyclophosphamide, Erythromycin, Testosterone
2C-family Acetaminophen, Tolbutamide (2C9); Hexobarbital, S-
Warfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin,
Zidovudine (2C8,9,19);
2E1 Acetaminophen, Caffeine, Chlorzoxazone, Halothane
2D6 Acetaminophen, Codeine, Debrisoquine
3A4 Acetaminophen, Caffeine, Carbamazepine, Codeine,
Cortisol, Erythromycin, Cyclophosphamide, S- and R-
Warfarin, Phenytoin, Testosterone, Halothane, Zidovudine
Non-CYP Drug Oxidations
• Monoamine Oxidase (MAO), Diamine Oxidase (DAO)
• MAO (mitochondrial) oxidatively deaminates endogenous
substrates including neurotransmitters
• Dopamine, serotonin, norepinephrine, epinephrine

• Alcohol & Aldehyde Dehydrogenase

• Non-specific enzymes found in soluble fraction of liver
• Ethanol metabolism

• Flavin Monooxygenases
• Require molecular oxygen, NADPH, flavin adenosine dinucleotide
(FAD)
 2. Reduction :
Reduction
Enzymes responsible for reduction of xenobiotics require NADPH as a
cofactor. Substrates for reductive reactions include azo- or nitrocompounds,
epoxides, heterocyclic compounds, and halogenated hydrocarbons:

(a) Azo or nitroreduction by cytochrome P450;

(b) Carbonyl (aldehyde or ketone) reduction by aldehyde reductase, aldose
reductase, carbonyl reductase, quinone reductase
(c) other reductions including disulfide reduction, sulfoxide reduction, and
reductive dehalogenation.
The acceptance of one or more electron(s) or their equivalent from another
substrate.
Reductive reactions, which usually involve addition of hydrogen to the drug
molecule, occur less frequently than the oxidative reactions.
 Biotransformation by reduction is also capable of generating polar functional
groups such as hydroxy and amino groups, which can undergo further
biotransformation.
Many reductive reactions are exact opposite of the oxidative reactions
(reversible reactions) catalysed cither by the same enzyme (true reversible
reaction) or by different enzymes (apparent reversible reactions).
Such reversible reactions usually lead to conversion of inactive metabolite into
active drug, thereby delaying drug removal from the body.
Reduction of Aldehydes and Ketones Carbonyls
 The carbonyl moiety, particularly the ketone group, is
encountered frequently in many drugs.
 Aldehydes are reduced to primary alcohols.
 Ketones, however, are generally resistant to oxidation and are reduced mainly to secondary
alcohols.
 Enzymes, called aldo-keto reductases, carry
out bioreduction of aldehydes and ketones.
They are found in the liver and other tissues
e.g. kidney.
 Oxidoreductase enzymes that carry out both
oxidation and reduction reactions also can
reduce aldehydes and ketones.
 For example, the important liver alcohol
dehydrogenase is an NAD+ dependent
oxidoreductase that oxidizes ethanol and other
aliphatic alcohols to aldehydes and ketones.
 In the presence of NADH or NADPH, however,
the same enzyme system can reduce carbonyl
derivatives to their corresponding alcohols.
 Few aldehydes undergo bioreduction because of the relative ease of oxidation of
aldehydes to carboxylic acids.
 example of aldehydes drug undergoing extensive enzymatic reduction is the
sedative–hypnotic chloral hydrate.
 Bioreduction of this hydrated aldehyde yields
trichloroethanol as the major metabolite in humans.
 Interestingly, this alcohol metabolite is pharmacologically active.
 Further Glucuronidation of the alcohol leads to an inactive conjugated product
that is readily excreted in the urine
 Reduction of Nitro and Azo Compound
 The reduction of aromatic nitro and azo xenobiotics leads to aromatic primary
amine metabolites.
 Bioreduction of nitro compounds is carried out by NADPH- dependent
microsomal and soluble nitro reductases present in the liver.
 A multicomponent hepatic microsomal reductase system requiring NADPH
appears to be responsible for azo reduction.
 In addition, bacterial reductases present in the intestine can reduce nitro and azo
compounds, especially those that are absorbed poorly or excreted mainly in the
bile.
 Miscellaneous Reduction
 Sulfoxide functionalities are oxidized
mainly to sulfones (-SO2-), they sometimes
undergo reduction to sulfides.

 The importance of this reductive pathway is seen in the

metabolism of the anti-inflammatory agent sulindac.
 Studies in humans show that sulindac undergoes reduction to an active
sulfide that is responsible for the overall anti inflammatory effect of the
parent drug.
 Sulindac or its sulfone metabolite exhibits inflammatory activity.
 Hydrolysis of Esters and amides
 The metabolism of ester and amide linkages in many drugs is catalyzed by
hydrolytic enzymes present in various tissues and in plasma.
 The metabolic products formed generally are polar and functionally more
susceptible to conjugation and excretion than the parent ester or amide drugs.
 Hydrolysis is a major biotransformation pathway for drugs containing an ester
functionality.
 A classic example of ester hydrolysis is the metabolic conversion of aspirin
(acetylsalicylic acid) to salicylic acid.
 Of the two ester moieties present in cocaine, it appears that,
in general,
 The methyl group is hydrolyzed preferentially to yield
benzoylecgonine as the major human urinary metabolite.
 The hydrolysis of cocaine to methyl ecgonine, however, also occurs in
plasma and, to a minor extent, blood.
 Amides are hydrolyzed slowly in comparison to esters.
 Consequently, hydrolysis of the amide bond of procainamide is
relatively slow compared with hydrolysis of the ester linkage in
procaine.
4. Cyclization
• Formation of ring structure from a straight chain
compound
• E.g. Proguanil

5. Decyclization
• Opening up of ring structure of the cyclic drug
molecule
• E.g. Barbiturates, Phenytoin.
 PHASE II REACTIONS

 Phase II or conjugation reactions involve combination of the drug

or its phase I metabolite with an endogenous substance to form
a highly polar product, which can be efficiently excreted from
the body.

 In the biotransformation of drugs, such products or metabolites

have two parts:
 Exocon, the portion derived from exogenous compound or
xenobiotic,
 Endocon, the portion derived from endogenous substance.

 Conjugation reactions have high energy requirement and they

often utilise suitable enzymes for the reactions.
 The endogenous substances (endocons) for conjugation reactions are
derived mainly from carbohydrates or amino acids and usually possess large
molecular size.
 They are strongly polar or ionic in nature in order to render the substrate
water-soluble. The molecular weight of the conjugate (metabolite) is important
for determining its route of excretion.
 High molecular weight conjugates are excreted predominantly in bile (e.g.,
glutathione exclusively, glucuronide mainly),
 while low molecular weight conjugates are excreted mainly in the urine.
 As the availability of endogenous conjugating substance is limited, saturation of
this process is possible and the unconjugated drug/metabolite may precipitate
toxicity.
1. Conjugation with glucuronic acid
Also Called as Glucuornidation, is the most common and most important phase II
reaction for several reasons:
a. Readily available source of conjugating moiety, D – Glucuornic acid which is
derived from D-Glucose.
b. Several functional groups such as alcohols, acids, amines etc. can combine
easily with D- Glucuronic acid.
c. Quantitatively, conjugation with D-glucuronic acid occurs to a high degree.
d. All amines have the common ability to produce glucuronides.
e. The free carboxyl function of glucuronic acid has a pKa in the range 3.5 to 4.0
and hence ionisable at both plasma and urine pH thereby generally increasing
the water solubility of the conjugated substrate.
f. Glucuronidation can take place in most body tissues because the glucuronic
acid donor UDPGA is present in abundant quantity in body, unlike donors
involved in other phase II reactions.
Glucuornide Formation occurs in 2 Steps:
Conjugation with sulphate/ Sulphation:

• Conjugation with sulphate (sulphate conjugation, sulphoconjugation

orsulphation) is similar to glucuronidation but is catalysed by non-
microsomal enzymes and occurs less commonly.
• The endogenous donor of the sulphate group is 3'- phosphoadenosine-5'-
phosphosulphate (PAPS), and enzyme catalysing the reaction is
sulphotransferase.
• Sulphation also occurs in two steps:
3. Conjugation with glutathione and mercapturic acid formation.

• Glutathione (γ – glutamyl cysteinyl glycine or GSH) is a tripeptide with a strongly

nucleophilic character due to the presence of a –SH group in its structure.

• Thus, it has great affinity for electrophile substartes, a number of which are potentially
toxic compounds.
• It is important to note that highly electrophile metabolite has a tendency to react with
tissue nucleophilic gropus such as –OH, NH2, and –SH.
• Conjugate with glutathione protects the tissue such reactive moieties and thus, the
reaction is important detoxication route.
Conjugation with methyl group/ Methylation

• Conjugation with methyl group (methyl conjugation or methylation) involves

transfer of a methyl group (-CH3) from the cofactor S-adenosyl methionine
(SAM) to the acceptor substrate by various methyl transferase enzymes.
• Methylation reaction is of lesser importance for drugs, but is more important
for biosynthesis (e.g., adrenaline, melatonin) and | Inactivation (e.g., histamine)
of endogenous amines.
• Occasionally, the metabolites formed are not polar or water- soluble and may
possess equal or greater activity than the parent compound (e.g., adrenaline
synthesised from noradrenaline).
Conjugation with acetyl group/ Acetylation :
 Conjugation with acetyl group (acetylation) is an important metabolic pathway
for drugs containing the amino groups.

 The cofactor for these reactions is acetyl coenzyme A and the enzymes are
non-microsomal N-acetyl transferases, located in the soluble fraction of cells
of various tissues.

 Acetylation is the primary route of biotransformation of sulphonamide

compounds.

 Acetylation is not a true detoxification process because occasionally it results

in decrease in water solubility of an amine and. thus, increase in its toxicity
(e.g., sulphonamides).
Conjugation with thiosulphate : Conjugation with thiosulphate is
an important reaction in the detoxification of cyanide. Conjugation
of cyanide ion involves transfer of sulphur atom from the
thiosulphate to the cyanide ion in presence of enzyme rhodancse
to form inactive thiocyanate.

Thiocyanate formed is much less toxic than the cyanide (true

detoxification) and it is excreted in urine.
 INDUCTION OF METABOLISM
 Administration of certain xenobiotics sometimes results in a
selective increase in the concentration of metabolizing enzymes in
both phase I and II metabolism, and thereby in their activities
Enzyme induction becomes important especially when
polypharmacy involves drugs with narrow therapeutic windows, since
the induced drug metabolism could result in a significant decrease in
its exposure and therapeutic effects.
In addition, enzyme induction may cause toxicity, associated with
increased production of toxic metabolites.
Mechanisms of Induction
Stimulation of transcription of genes and/or translation of proteins,
and/or stabilization of mRNA and/or enzymes by inducers, resulting in
elevated enzyme levels.
Stimulation of preexisting enzymes resulting in apparent
enzyme induction without an increase in enzyme synthesis (this
is more common in vitro than in vivo).
In many cases, the details of the induction mechanisms are
unknown.
TWO receptors have been identified for CYPlA1/2 and
CYP4A1/2induction:
(a)Ah (aromatic hydrocarbon) receptor in cytosol, which
regulates enzyme (CYP1 A1 and 1A2) induction by polycyclic
aromatic hydrocarbon (PAH)-type inducers;
(b) Peroxisome proliferator activated receptor (PPAR), where
hypolipidemic agents cause peroxisome proliferation in rats
(CYP4A1 and 4A2);-humans have low PPAR and show no
effects from hypolipidemic agents.
 Characteristics of Induction
Induction is a function of intact cells and cannot be achieved by treating
isolated cell fractions such as microsomes with inducers.
Evaluation of enzyme induction is usually conducted in ex vivo experiments, ie.,
treating animals in vivo with potential inducers and measuring enzyme activities
in vitro or in cell-based in vitro preparations such as hepatocytes, liver slices, or
cell lines.
Recent studies have demonstrated that primary cultures of hepatocytes can be
used for studying the inducibility of metabolizing enzymes such as P450 under
certain incubation conditions
Enzyme induction is usually inducer-concentration–dependent. The extent of
induction increases as the inducer concentration increases; however, above
certain values, induction starts to decline.
In general, inducers increase the content of endoplasmic reticulum within
hepatocytes as well as liver weight.
In some cases, an inducer induces enzymes responsible for its own
metabolism (so-called “autoinduction”).
 Induction of Drug Metabolising Enzymes

 Several drugs and chemicals have ability to increase the drug

metabolising activity of enzymes called as enzyme induction.

 These drugs known as enzyme inducers mainly interact with DNA and
increase the synthesis of microsomal enzyme proteins, especially
cytochrome P-450 and glucuronyl transferase.

 As a result, there is enhanced metabolism of endogenous substances

(e.g., sex steroids) and drugs metabolised by microsomal enzymes.
Some drugs (e.g., carbamazepine and rifampicin) may stimulate their
own metabolism, the phenomenon being called as auto-induction or
self induction.
Since different cytochrome P450 isoenzymes are involved in the
metabolism of different drugs, enzyme induction by one drug affects
metabolism of only those drugs, which are substrate for the induced
isoenzyme.

However, some drugs like Phenobarbitone may affect metabolism of a

large number of drugs because they induce isoenzymes like CYP3A4 and
CYP2D6 which act on many drugs.

Enzyme inducers are generally lipid-soluble compounds with relatively long

plasma half-lives.

Repeated administration of inducers for a few days (3 to 10 days) is often

required for enzyme induction, and on stoppage of drug administration,
the enzymes return to their original value over 1 to 3 weeks.

Non-microsomal enzymes are not known to be induced by any drug or

chemical.
Clinical importance of enzyme induction

 It reduces efficacy and potency of drugs metabolised by these

enzymes.

 It reduces plasma half-life and duration of action of drugs.

 It enhances drug tolerance.

 It increases drug toxicity by enhancing concentration of

metabolite, if metabolite is toxic.

 It increases chances of drug interactions.

 It alters physiological status of animal due to altered metabolism

of endogenous compounds like sex steroids.
Inhibition of Drug Metabolising Enzymes

Contrary to metabolising enzyme induction, several drugs or chemicals

have the ability to decrease the drug metabolising activity of certain
enzymes called as enzyme inhibition.

Enzyme inhibition can be either non-specific of microsomal enzymes or

specific of some non-microsomal enzymes (e.g., monoamine oxidase,
cholinesterase and aldehyde dehydrogenase).

 The inhibition of hepatic microsomal enzymes mainly occurs due to

administration of hepatotoxic agents,
which cause either rise in the rate of enzyme degradation (e.g., carbon
tetrachloride and carbon disulphide) or fall in the rate of enzyme synthesis
(e.g., Puromycin and Dactinomycin).
Nutritional deficiency, hormonal imbalance or hepatic
dysfunction, etc.also inhibit microsomal enzymes indirectly.

Inhibition of non-microsomal enzymes with specific function

usually results when Structurally similar compounds compete for
the active site on the enzymes.

Such an inhibition is usually rapid (a single dose of inhibitor may

be sufficient) and clinically more important than the non- specific
microsomal enzyme inhibition.

Enzyme inhibition generally results in depressed metabolism of

drugs.
As a result, the plasma hall-life, duration of action, and efficacy
as well toxicity of the object drug (whose metabolism has been
inhibited) are significantly enhanced.
In case the drug undergoes hepatic first-pass effect, the
bioavailability and toxicity Of the drug will be markedly increased
in presence of enzyme inhibition. Enzyme inhibition may also
produce undesirable drug interactions.

 In therapeutics, some specific enzyme inhibitors like

monoamine oxidase inhibitors, cholinesterase inhibitors and
angiotensin converting enzyme (ACE) inhibitors are purposely
used for producing desirable pharmacological actions
 Inducing Agents
 In general, enzyme inducers are lipophilic at physiological pH and
exhibit relatively long t 1/2 with high accumulation in the liver.

Different classes of enzyme inducers.

1. Barbiturates: Phenobarbitone, Phenobarbital.
2.Polycyclic aromatic hydrocarbons (PAH): 3-methylcholanthrene (3-MC),
2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD), β-naphthoflavone β ( -NF).
3. Steroids: Pregnenalone 16-α -carbonitrile (PCN), Dexamethasone.
4. Simple hydrocarbons with aliphatic chains: Ethanol (chronic), Acetone,
5. Hypolipidemic agents: Clofibrate, lauric acids.
6. Macrolide antibiotics: Triacetyloleandomycin (TAO).
7.A wide variety of structurally unrelated compounds: e.g., Antipyrine,
Carisoniazid. Bamazepine, Phenytoin, and Rifampicin
 EXTRAHEPATIC METABOLISM
 Most tissues have some metabolic activity; however,
quantitatively the liver is by far the most important organ for drug
metabolism.

Important organs for extrahepatic metabolism include the

intestine (enterocytes and intestinal microflora), kidney, lung,
plasma, blood cells, placenta, skin, and brain.

In general, the extent of metabolism in the major extrahepatic

drug-metabolizing organs such as the small intestine, kidney, and
lung is approximately 10–20% of the hepatic metabolism.

Less than 5% of extrahepatic metabolism compared to hepatic

metabolism can be considered low with negligible
pharmacokinetic implications
 First-Pass Effect/First-Pass Metabolism

 First-pass effect (first-pass metabolism or pre-systemic metabolism) may be defined

as the loss of drug through biotransformation before it enters systemic circulation.

 This may occur during passage of drug for first time (therefore called first-pass
effect/metabolism) through intestine or liver after oral administration.

 Intestinal first-pass effect: In this type, drugs are metabolised in the gastrointestinal
tract by enzymes present in either gut mucosa or gut lumen before they are
absorbed
 Recent studies have indicated that P450 isoforms such as CYP2C19 and 3A4 in
enterocytes might play an important role in the presystemic intestinal metabolism of
drugs and the large interindividual variability in systemic exposure after oral
administration
 The cytochrome P450 content of the intestine is about 35% of the hepatic content in
the rabbit, but accounts for only 4% of the hepatic content in the mouse.
Cytochrome P450 levels and activities are highest in the duodenum near the
pyrolus, and then decrease toward the colon
 A similar trend in regional activity levels along the intestine has been observed for
glucuronide, sulfate, and glutathione conjugating enzymes.
 Microorganisms present in the GI tract also inactivate some drugs.
Such drugs are not suitable by oral administration due to poor
bioavailability (e.g., catecholamines).

 Hepatic first-pass effect: In this type, drugs are suitably absorbed

across the GI tract and enter portal circulation, but they are rapidly
and significantly metabolised during the first passage through the
liver.

 (Normally, when a drug is absorbed across GI tract, it first enters the

portal vein and passes through liver before it reaches the systemic
circulation).

 Such drugs are also not/less suitable by oral administration due to

their poor bioavailability. Examples of drugs undergoing significant
hepatic first-pass effect include Propranolol, Lignocaine and
Nitro•glycerine.
The rate and extent of first-pass intestinal metabolism of a drug
after oral administration are dependent on various physiological
factors
1.Site of absorption: If the absorption site in the intestine is different
from the metabolic site, first-pass intestinal metabolism of a drug may
not be significant.
2.Intracellular residence time of drug molecules in enterocytes: The
longer the drug molecules stay in the enterocytes prior to entering
the mesenteric vein, the more extensive the metabolism.
3.Diffusional barrier between splanchnic bed and enterocytes: The
lower the diffusibility of a drug from the enterocytes to the
mesenteric vein, the longer its residence time.
4.Mucosal blood flow: Blood in the splanchnic bed can act as a sink
to carry drug molecules away from the enterocytes, which reduces
intracellular residence time of drug in the enterocytes
 Renal Metabolism
In addition to physiological functions of homeostasis in water and
electrolytes and the excretion of endogenous and exogenous compounds
from the body, the kidneys are the site of significant biotransformation
activities for both phase I and phase II metabolism.
The renal cortex, outer medulla, and inner medulla exhibit different
profiles of drug metabolism, which appears to be due to heterogeneous
distribution of metabolizing enzymes along the nephron.
Most metabolizing enzymes are localized mainly in the proximal tubules,
although various enzymes are distributed in all segments of the nephron
The pattern of renal blood flow, pH of the urine, and the urinary
concentrating mechanism can provide an environment that facilitates the
precipitation of certain compounds, including metabolites formed within the
kidneys.
The high concentration or crystallization of xenobiotics and/or their
metabolites can potentially cause significant renal impairment in specific
regions of the kidneys.
 Metabolism in Blood
 Blood contains various proteins and enzymes.
As metabolizing enzymes, esterases, including cholinesterase,
arylesterase, and carboxylesterase, have the most significant effects
on hydrolysis of compounds with ester, carbamate, or phosphate
bonds in blood .
Esterase activity can be found mainly in plasma, with less activity in
red blood cells.
Plasma albumin itself may also act as an esterase under certain
conditions.
For instance, albumin contributes about 20% of the total hydrolysis
of aspirin to salicylic acid in human plasma.
The esterase activity in blood seems to be more extensive in small
animals such as rats than in large animals and humans. Limited, yet
significant monoamine oxidase activities can be also found in blood.
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