3837Biotransformation (Metabolism) of Drugs

7/27/2019 3837Biotransformation (Metabolism) of Drugs

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Biotransformation

(Metabolism) of Drugs


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A. General properties

1. Biotransformation is a major mechanism fordrugelimination;

Results of biotransformation:

Production of metabolites that are more polar thanthe parent drug

usually terminates the pharmacologic action of theparent drug

After phase I reactions, similar or different

pharmacologic activity, or toxicologic activity.


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Results of biotransformation


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2. Many drugs undergo

several sequential biotransformation reactions.

Biotransformation is catalyzed by specific enzyme systems

3. Sites of biotransformation:

The liver: the major site

other tissues.


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4. Biotransformation of drugs can be affected by manyparameters, including:

A. prior administration of the drug in question or of other drugs

B. diet

C. hormonal status

D. genetics

E. disease (e.g., decreased in cardiac and pulmonary disease)F. age and developmental status

G. liver function


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5. Possible consequences of biotransformationinclude the production of:

inactive metabolites (most common)

metabolites with increased or decreased potencies

metabolites with qualitatively differentpharmacologic actions

toxic metabolites

active metabolites from inactive prodrugs.


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Metabolites are often more polarthan the parent

compounds.

This increased polarity may lead to:

a more rapid rate of clearance because of possible

secretion by acid or base carriers in the kidney

it may lead to decreased tubular reabsorption.


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B. Classification of biotransformation reactions

1. Reactions that involve enzyme-catalyzedbiotransformation of the drug without any conjugations.

Phase I reactions include:

oxidations reductions

hydrolysis reactions

they introduce a functional group (e.g., -OH) that serves

as the active center for sequential conjugation in aphase II reaction.


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2. Reactions that include conjugation reactions, which

involve the enzyme-catalyzed combination of a drug (or

drug metabolite) with an endogenous substance.

Phase II reactions require:

a functional groupanactive centeras the site of

conjugation with the endogenous substance.

energyindirectly for the synthesis of activated

carriers, the form of the endogenous substance used

in the conjugation reaction (e.g., UDP-glucuronate).


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Drug metabolism reactions :


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C. Enzymes catalyzing phase I biotransformation

reactions

Enzymes catalyzing phase I biotransformationreactions include:

cytochrome P-450

aldehyde and alcohol dehydrogenase

deaminases

esterases

amidases

epoxide hydratases


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Enzymes catalyzing phase II biotransformation

reactions include:

glucuronyl transferase (glucuronide conjugation)

sulfotransferase (sulfate conjugation) transacylases (amino acid conjugation)

acetylases

ethylases

methylases

glutathione transferase.


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Location of these enzymes:

numerous tissues

some are present in plasma.

Subcellular locations include:

cytosol

mitochondria

endoplasmic reticulum

Only those enzymes located in the endoplasmic

reticulum are inducible by drugs


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1. Cytochrome P-450 monooxygenase

(mixed function oxidase)

a. General features

A large number of families (at least 18 in mammals) ofcytochrome P-450 (abbreviated CYP) enzymes

exists each member of which catalyzes the biotransformation

of a unique spectrum of drugs

some overlap in the substrate specificities.

This enzyme system is the one most frequentlyinvolved in phase I reactions.


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The cytochrome P-450 families are referred to usingan arabic numeral, e.g., CYP1, CYP2, etc.

Each family has a numberof subfamilies denoted by

an upper case letter, e.g., CYP2A, CYP2B, etc.

The individual enzymes within each subfamily aredenoted by another arabic numeral, e.g., CYP3A1,CYP3A2, etc.


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Cytochrome P-450 catalyzes numerous reactions,including:

aromatic and aliphatic hydroxylations

dealkylations at nitrogen, sulfur, and oxygen atoms heteroatom oxidations at nitrogen and sulfur atoms

reductions at nitrogen atoms

ester and amide hydrolysis


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The CYP3A subfamily is:

responsible for up to half of the total cytochrome P-450 in the liver

accounts for approximately 50% of the metabolism ofclinically important drugs.

CYP3A4is a particularly abundant enzyme.


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representative P450 isozymes.


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b. Localization

The primary location of cytochrome P-450 is the liver,

Other tissues, including: the adrenals

ovaries and testis

tissues involved in steroidogenesis and steroid metabolism.

The enzyme's subcellular location is the endoplasmicreticulum.


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c. Mechanism of reaction

1. In the overall reaction:

the drug is oxidized

oxygen is reduced to water.

Reducing equivalents are provided by nicotinamide

adenine dinucleotide phosphate (NADPH), and

generation of this cofactor is coupled to cytochrome

P-450 reductase.


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d. Genetic polymorphisms

Genetic polymorphism of several clinically importantcytochrome P-450s, particularly CYP2Cand CYP2D,

is a source of variable metabolism in humans,including differences among racial and ethnic groups.

These enzymes have substantially different properties

(V

max orK

m).


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e. Induction of drug metabolism :

Enzyme synthesis initiated within 24 h of exposure,increasing over 35 days

Effect decreases over 13 weeks after inducing agentis discontinued

Environmental Factors:Cigarette smoking

eating BBQ meat

cruciferous veggies (plants in the mustard family whichincludes the cabbage, radish, broccoli, and many weeds.)

high protein diet

Ethanol

exposure to insecticides (DDT, Lindane) & PCBs

(polychlorinated biphenyls)


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Other drugs: Barbiturates

Phenytoin

Carbamazepine Rifampicin

dexamethasone


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f. Inhibition

Rapid onset within 1 day

Competitive or noncompetitive (clinically more likely)inhibition of P-450 enzyme activity can result in thereduced metabolism of other drugs or endogenoussubstrates such as testosterone.

Inhibition can be caused by a number ofcommonlyused drugs, including:

Cimetidine fluconazole

Fluoxetine

Erythromycin

grapefruit juice.


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Glucuronyl Transferse

1. General features

Glucuronyl transferase is a set of enzymes withunique but overlapping specificities that are involvedin phase II reactions.

It catalyzes the conjugation of glucuronic acid to avariety of active centers, including: -OH

-COOH -SH

-NH2


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2. Mechanism of reaction UDP-glucuronic acid, the active glucuronide donor, is formed

from UTP and glucose 1-phosphate.

Glucuronyl transferase then catalyzes the conjugation to theactive center of the drug.

3. Location and induction Glucuronyl transferase is located in the endoplasmic

reticulum.

It is the only phase II reaction that is inducible by drugs and isa possible site of drug interactions.


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Metabolism of phenytoin :


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Inhibitors of intestinal P glycoprotein:

P-glycoprotein (P-gp) has been identified as animportant modulator of intestinal drug transport andusually functions to expel drugs from the intestinalmucosa into the lumen.

Drugs that inhibit intestinal P-gp mimic drugmetabolism inhibitors by increasing bioavailability andmay result in toxic plasma concentrations of drugsgiven at normally nontoxic dosage.


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P-gp inhibitors include:

Verapamil

grapefruit juice

Important drugs that are normally expelled by P-gp (andwhich are therefore potentially more toxic when givenwith a P-gp inhibitor) include digoxin, cyclosporine, andsaquinavir.


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Metabolism of acetaminophen to harmless conjugates or to toxic metabolites.

nontoxic phase II conjugatesnontoxic phase II conjugates

toxic

phase I ReactionAc* production increases:

1. Depletion of hepatic stores

of sulfate, glucuronide, and

glutathione

2. Overwhelm phase II rxns3. Induction of phase I enzymes

3837Biotransformation (Metabolism) of Drugs

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