Site hosted by Build your free website today!

                              DRUG METABOLISM(Biotransformation)



                                          BY. MUHAMMAD BILAL MIRZA 4th YEAR PMC. 

?   Introduction

o Lipophilic drug properties that promote passage through biological membranes and facilitate reaching site to drug action, inhibit drug excretion.

? Note: renal excretion of unchanged drug contributes only slightly to elimination, since the unchanged, lipophilic drug is easily reabsorbed through renal tubular membranes.

o Biotransformation of drugs to more hydrophilic molecules is required for elimination of the drug from the body

? Biotransformation reactions produce more polar, hydrophilic, biologically inactive molecules -- that are more readily excreted.

? Sometimes metabolites retain biological activity and may be toxic.

? Drug Biotransformation mechanisms are described as either phase I or phase II reaction types.


?   Phase I and Phase II Reactions -- 

o Phase I characteristics:

? Parent drug is altered by introducing or exposing a functional group (-OH,-NH2, -SH)

? Drugs transformed by phase I reactions usually lose pharmacological activity

? Inactive, prodrugs are converted by phase I reactions to biologically-active metabolites

? Phase I reaction products may:

? Be directly excreted in the urine

? React with endogenous compounds to form water-soluble conjugates.


o Phase II characteristics:

? Parent drug participates in conjugation reactions that is  formation of  covalent linkage between a parent compound functional group and:

? Glucuronic acid

? Sulfate

? Glutathione

? Amino acids

? Acetate

  Conjugates are:

? Highly polar

? Generally inactive

? Exception to the rule: morphine glucuronide metabolite-- which is more potent analgesic then parent compound

? Rapidly excreted in the urine

? High molecular weight conjugates:

?       Excreted in the bile

?       Conjugate bond may be cleaved by intestinal flora

?       Parent drug released back to the systemic circulation

?      Through a process, "enterohepatic recirculation" which causes

?      Delayed parent drug elimination

?       Prolongation of drug effect

Principal Organs for Biotransformation:

?   Principal Organ: It is  Liver

o Other metabolizing organs: are

? Gastrointestinal tract

? Lungs

? Skin

? Kidney

?   Sequence I

o A.     Oral administration (isoproterenol (Isuprel), meperidine (Demerol), pentazocine (Talwain), morphineisoproterenol)

o B.     Absorbed from small intestine

o C.     Transported first to the liver (portal system) and

o D.     Extensive metabolism called-- first-pass metabolism.

?   Sequence II

o .        Oral administration: (clonazepam (Klonopin), chlorpromazine (Thorazine))

o A.     Absorbed intact (small intestine)

o B.     Extensive intestinal metabolism -- contributing to overall first-pass effect

?    Issues in bioavailability: reduced bioavailability is due to

o First pass effect: bioavailability of orally administered drugs  become very small-- so-- alternative routes of administration must be used

o Intestinal flora may metabolize drugs

o Instability of the drug  in gastric acid--  as in case of penicillin

o Metabolized by digestive enzymes -- as in case of insulin

o Metabolized by intestinal wall enzymes-- as in case of sympathomimetic catecholamines


Mixed function oxidase System (cytochrome 450 System)--Phase I Reactions

?    Microsomes have been used to study mixed function oxidases

o Drug metabolizing enzymes:

? Located in lipophilic, hepatic endoplasmic reticulum membranes

? Smooth endoplasmic reticulum: contains enzymes responsible for drug metabolism 

o The reaction:

? One molecule oxygen is consumed per substrate molecule

? One oxygen atom -- appears in the product; the other in the form of water

? Oxidation-Reduction Process:

? Two important microsomal enzymes are involved in this process

 A. Flavoprotein--NADPH cytochrome P450 reductase

B.   Cytochrome P450: -- terminal oxidase                                                                                  Cytochrome P450 Enzyme Induction:

o Following repeated administration, some drugs induce cytochrome P450 (increase amount of P450 enzymes) usually by:

? Increase enzyme synthesis rate

? Reduced enzyme degradation rate

                                           Cytochrome P450 enzyme inhibition:

o Certain drugs, by binding to the cytochrome component, act to competitively inhibit metabolism. Examples:

? Cimetidine (Tagamet) (anti-ulcer --H2 receptor blocker) and Ketoconazole (Nizoral) (antifungal) bind to the heme iron a cytochrome P450, reducing the metabolism of:

? testosterone

? other co administered drugs

? Mechanism of Action: competitive inhibition

o Catalytic inactivation of cytochrome P450.

? Macrolide antibiotics (troleandomycin, erythromycin estolate (Ilosone)), metabolized by a cytochrome P450:

? metabolites complex with cytochrome heme-iron: producing a complex that is catalytically inactive.

? Chloramphenicol (Chloromycetin): metabolized by cytochrome P450 to an alkylating metabolite that inactivates cytochrome P450

? Other inactivators: Mechanism of Action: -- targeting the heme moiety:

? steroids:

? ethinyl estradiol (Estinyl)

? norethindrone (Aygestin)

? spironolactone (Aldactone)

? others:

? propylthiouracil

? ethchlorvynol (Placidyl)


Phase II Metabolism


Some Phase II Reactions

Type of Conjugation

Endogenous Reactant

Transferase (Location)

Types of Substrates



UDP glucuronic acid

UDP glucuronosyl transferase (microsomal)

phenols, alcohols, carboxylic acids, hydroxylamines, sulfonamides

morphine, acetaminophen, diazepam, digitoxin, digoxin, meprobamate



N-Acetyl transferase (cytosol)


sulfonamides, isoniazid, clonazepam, dapsone, mescaline

Glutathione conjugation


GSH-S-transferase (cytosolic, microsomes)

epoxides, nitro groups, hydroxylamines

ethycrinic acid, bromobenzene

Sulfate conjugation

Phosphoadenosyl phosphosulfate

Sulfotransferase (cytosol)

phenols, alcohols, aromatic amines

estrone, 3-hydroxy coumarin, acetaminophen, methyldopa



transmethylases (cytosol)

catecholamines, phenols, amines, histamine

dopamine, epinephrine, histamine, thiouracil, pyridine



?    Overview: Phase II reactions: on-microsomal enzymes

o Reaction types:

1.   Conjugation

2.   Hydrolysis

3.   Oxidation

4.   Reduction

o Location (non-microsomal enzymes): primarily hepatic (liver); also plasma & gastrointestinal tract

o Non-microsomal enzymes catalyze all conjugation reactions except glucuronidation

Nonspecific esterases in liver, plasma, and gastrointestinal tract hydrolyzed drugs containing ester linkages, e.g.:

Nonspecific esterases in liver, plasma, gastrointestinal tract hydrolyzed drugs containing ester linkages, e.g.:

succinylcholine (Anectine)

atracurium (Tracrium)

mivacurium (Mivacron)

esmolol (Brevibloc)

Ester-type local aesthetics


Conjugation reactions: Usually "detoxification reaction

?    Conjugates: are

o more polar

o easily excreted

o typically inactive

?    Conjugation:

o Involves "high-energy" intermediates and specific transfer enzymes (microsomal or cytosolic transferases)

o   Conjugation with glucuronic acid requires cytochrome P450 enzymes.

? glucuronic acid: available from glucose

? glucuronic acid conjugated to lipid-soluble drug results in lipophilic glucuronic acid derivative:

? pharmacologically inactive

? more water-soluble; more easily excreted in urine & bile

o Transferases:

? catalyzes coupling of an endogenous substance with a drug

? uridine-5'-diphosphate (UDP) derivative of glucuronic acid with a drug

? catalyzes inactivated drug within endogenous substrate

? for example: S-CoA derivative of benzoic acid within endogenous substrate.




?    Toxicity:

o Certain conjugation reactions: form toxic reactive species (hepatotoxicity)

? Example:

1.   acyl glucuronidation nonsteroidal antiinflammatory drugs

2.   N-acetylation of isoniazid

o Drugs metabolized to toxic products:

? Acetaminophen hepatotoxicity -- normally safe in therapeutic doses

? Therapeutic doses:

1. Glucuronidation + sulfation to conjugates (95% of excreted metabolites); 5% due to alternative cytochrome P450 depending glutathione (GSH) conjugation pathway

? At high doses:

1. Glucuronidation and sulfation pathways become saturated

2. Cytochrome P450 dependent pathway: now more important

? with depletion of hepatic glutathione, hepatotoxic, reactive, electrophilic metabolites are formed

  Antidotes:      is N-acetylcysteine, cysteamine

            N-acetylcysteine: protects patients from fulminant hepatotoxicity and death following acetaminophen overdose



Correia, M.A., Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, Benet, Leslie Z, Kroetz, Deanna L. and Sheiner,Goodman and Gillman's The Pharmacologial Basis of Therapeutics, TheMcGraw-Hill Companies, Lippincott's pharmacology.