Drug Metabolism Flashcards by Eb Nac

body’s mechanism for processing, using, inactivating, and
eventually eliminating foreign substances, including drugs.

Metabolism i

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recognizes the drug as a
foreign substance can break down or alter the chemical structure of drugs,
making them less active, or inert.

liver,
the blood, the lymph fluid, or any body tissue

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role of these enzymes is to
degrade or modify the foreign structure, such that it can be more
easily excreted.

metabolic enzymes

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defined as any
foreign substances or exogenous chemicals which the body does not recognize such as drugs, pollutants, others

Xenobiotics

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once in the bloodstream, these molecules can ———– through other membranes and be distributed
effectively to reach various target organs to exert their pharmacological actions.

diffuse passively

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for excretion

water soluble

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for metabolism

lipophilic

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Consequences of Drug Metabolism

May yield inactive metabolites (“detoxification of the drug”)
May retain similar activity
May produce metabolites with altered activity
Production of bioactivated metabolites

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Hydrolysis of procaine to p- aminobenzoic acid & diethylethanolamine

(loss of anesthetic activity)

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Oxidation of 6- mercaptopurine to 6- mercapturic acid

(loss of anticancer activity

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Imipramine is demethylated

equally active antidepressant, desipramine

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Acetohexamide is reduced

more active hypoglycemic, I- hydroxyhexamide

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Codeine is demethylated

more active analgesic, morphine

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Hydroxyzine (an antihistamine) can be metabolized

Cetirizine

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antidepressant, Iproniazid is dealkylated

antitubercular drug, Isoniazid

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retinoic acid (Vitamin A) is isomerized

anti- acne agent, isoretinoic acid

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parent compounds

prodrugs

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prodrug enalapril is hydrolyzed

enalaprilat

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prodrug sulindac, a sulfoxide, is reduced

active sulfide (antibacterial)

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antiparkinsonian levodopa (L- dopa) is decarboxylated

active dopamine

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Sites of Drug Metabolism

Liver
Extrahepatic Metabolism

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primary site of drug metabolism, functions to detoxify and facilitate excretion of xenobiotics (foreign
drugs or chemicals) by enzymatically converting lipid-soluble compounds to more water-soluble compounds.

liver

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protect the organism against an accumulation of lipidsoluble exogenous and endogenous compounds by converting them to water-soluble metabolites which can be
easily excreted by the kidney are enymes located in

endoplasmic reticulum of liver cells

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present in the liver are responsible for much of drug
metabolism

Cytochrome P450 enzyme species

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affect the rate of metabolism of a person.

liver cirrhosis, liver cancer, fatty liver disease, hepatitis,

drug biotransformation/ metabolism that takes place in tissues other than the liver

Extrahepatic Metabolism

Plasma Intestinal mucosa Intestinal bacterial flora Stomach Nasal mucosa

Contains esterase enzymes which are responsible primarily for the hydrolysis of esters

Plasma

can activate a variety of prodrugs

, plasma esterases

Lipid- soluble drug passes through the intestinal mucosa which contains enzymes such as CYP 34A

Intestinal mucosa

Drug can be metabolized even before entering the blood

first pass effect

examples of drugs that easily undergo first- pass effect

imipramine lignocaine beta blockers morphine testosterone Salbutamol Cimetidine Diazepam Morphine

converts vitamin precursor to their active forms convert certain substances to their toxic forms

Bacterial flora

enzyme that Intestinal flora produces which can also be responsible for metabolism

azoreductase

Intestinal bacterial flora secrete enzyme which can metabolize drugs

beta- glucuronidase

Has enzymes necessary for metabolism and has an acidic environment

Stomach

Provides a high level of CYP450 enzymes that can cause metabolism

Nasal mucosa

microsomal superfamily of isoenzymes that catalyzes the oxidation of many drugs.

cytochrome P-450 (CYP450)

enzymes metabolize 90% of drugs.

CYP1A2 (2%), CYP2C9 (15%), CYP2C19 (15%), CYP2D6 (25%), CYP3A4 (60%), and CYP3A5 (2%)

true or false : Drugs may be metabolized by only one CYP450 enzyme (e.g., metoprolol by CYP2D6) or by multiple enzymes (e.g., warfarin [Coumadin] by CYP1A2, CYP2D6, and CYP3A4)

true

With aging, the liver’s capacity for metabolism through the CYP450 enzyme system is reduced by ------- because hepatic volume and blood flow are decreased.

≥ 30%

commonly due to impairments in the state of the enzymatic systems.

Qualitative changes

evolve in two directions:

Quantitative changes

the stimulation of enzymatic activity

(enzyme induction

the reverse, a reduction in enzyme activity

(enzyme inhibition

drug that causes change

precipitant drug

drug that undergoes change

object drug

block the metabolic activity of one or more CYP450 enzymes. The extent to which an inhibitor affects the metabolism of a drug depends upon factors such as the dose and the ability of the inhibitor to bind to the enzyme.

Inhibitors

increase CYP450 enzyme activity by increasing enzyme synthesis. Unlike metabolic inhibition, there is usually a delay before enzyme activity increases, depending on the half-life of the inducing drug

Inducers

These will slow down substrate drug metabolism and increase drug effect.

Enzyme inhibitor

These will speed up substrate drug metabolism and decrease drug effect.

Enzyme inducer

Phase I Metabolic Reactions

(Functionalization Reaction Phase)

Phase II Metabolic Reactions

(Conjugation Reaction Phase)

phase I reactions

oxidative processes (aromatic hydroxylation; aliphatic hydroxylation; N—, O—, and S-dealkylation; N-hydroxylation; N-oxidation; sulfoxidation; deamination; and dehalogenation), reductive (azoreduction, nitroreduction) hydrolytic reactions.

purpose of these phase 1 metabolism reactions is to produce a compound with

increased polarity and enhanced water solubility.

reactions undergone depend on;

nature of the available enzymes, ii. the hydrocarbon skeleton of the drug and iii. the functional groups present.

Phase I metabolic reactions are done by either of two ways:

Direct introduction of a functional polar group into the xenobiotic molecule; or ii. Modifying or "unmasking" existing functionalities

first step of drug metabolism.

Oxidation

Conversion of a hydrogen to a hydroxyl group.

hydroxylation

Conversion of a hydroxyl group to a carbonyl group

R-C-OH ⇒ R-C=O (dehydrogenation)

Conversion of a carbonyl group to a carboxyl group.

* R-C=O ⇒ R-COOH (carboxylation)

R-C-NH2⇒R-C=O Conversion of an amino group to a carbonyl group

.(deamination)

R-CH3⇒ R-H

(demethylation)

enzymes of oxidation

mixed-function oxidases, monoxygenases, cytochrome P450 enzymes.

Reactions resulting in the addition of hydrogen and/or the removal of oxygen

Reduction

R-OH ⇒ R-H

(de-hydroxylation)

* R-C=O ⇒ R-C-OH

(hydrogenation)

(decarboxylation)

R-COOH ⇒ R-C=O

R-NO2⇒ R-NH2

(amination)

R-C-H ⇒ R-CH3

(methylation)

Enzymes involved in reduction reactions

reductases

In a reaction with water, a bond in the compound is broken, resulting in two compounds. At the same time the water molecule splits in two, with a hydrogen transferring to one of the compounds and a hydroxide to the other compound.

Hydrolysis

R-COO-R' + H2O

R-COOH + R’-OH

R-CO-NH-R' + H2O

e enzymes of hydrolysis reactions

esterases, peptidases, and amidases.

synthetic reactions where the product or the metabolite from Phase I gets conjugated. This always produces a large, polar, metabolite that is readily excreted from the body.

Conjugation reactions a

Phase II reactions

glucuronidation, sulfation, amino acid conjugation, acetylation, methylation or glutathione conjugation to facilitate elimination

Glucuronidation Co- enzyme: Transfer enzyme:

Co- enzyme: UDP-GA (Uridine diphosphateglucuronic acid) Transfer enzyme: UDP (Uridine diphosphate) glucuronyl transferase

Glucuronidation Most Susceptible Functional Groups

-OH, -COOH, -NH2, -SO2NH2

Sulfation Co-enzyme: Trasnfer enzyme:

Co-enzyme: PAPS (3’-Phosphoadenosine-5’- phosphosulfate) Trasnfer enzyme: sulfotransferases

Sulfation Most Susceptible Functional Groups

-OH, -NH2, -SO2NH2, -NHOH

Glutathione Conjugation Transfer enzyme

Transfer enzyme: Glutathione-S-transferase

Amino acid Conjugation Co-enzyme Transfer enzyme

Co-enzyme: acyl-CoA synthetase Transfer enzyme: N-acetyltransferase

Acetylation Co-enzyme Transfer enzyme

Co-enzyme: acyl-CoA synthetase Transfer enzyme: N-acetyltransferase

Methylation Transfer enzyme:

Transfer enzyme: methyltransferases

Glutathione Most Susceptible Functional Groups

Alkyl halides, alkyl nitrates, epoxides, lactones, electrophilic centers

Amino acid Conjugation Most Susceptible Functional Groups

-COOH, -NH2

Acetylation Co-enzyme Most Susceptible Functional Groups

-OH, -NH2, -SO2NH2, -NHOH, -NHNH2

Methylation Most Susceptible Functional Groups

-OH, NH2, -SH

Active metabolite of the prodrug simvastatin

B-hydroxy acid metabolite

Active metabolite of the prodrug Capacitabine

Fluorouracil

Active metabolite of the prodrug Ramipril

Ramiprilat

Active metabolite of the prodrug of Terfenadine

Fexofenadine

Allopurinol

Oxypurinol

Active metabolite of the prodrug of Bambuterol

Terbutaline

Nabumetone

6 methoxy-2-naphthylacetic acid