DRUG METABOLISM(Biotransformation)

                                              

                                       doctorbilalmirza@yahoo.com

                                          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.

   Overview

?   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

 

 

 

?    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.:

•  

 

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

 

   REFERENCES

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.