Metabolic Changes in Drugs

Chapter 3

Organic Medicinal and Pharmaceutical Chemistry 12th Edition

Xenobiotics

O substances foreign to the body

O include environmental pollutants, food additives, cosmetic chemicals, agrochemicals, processed foods, and DRUGS.

O substances entering the body are relatively LIPOPHILIC (fat-loving or lipid soluble)

Xenobiotics

O If lipophilic drugs were not metabolized to polar, readily excretable products, they would remain indefinitely in the body, eliciting their biological effects. Hence,

No Metabolism Accumulation Toxicity

Drug Metabolism

O Diagram (Refer to your notes)

Drug Metabolism

O conversion of lipophilic (hydrophobic) compounds into hydrophilic (lipophobic) derivatives that are readily eliminated in urine or bile.

Drug Metabolism

O the formation of water-soluble metabolites not only enhances drug elimination, but also leads to compounds that are generally pharmacologically inactive and relatively nontoxic.

Drug Metabolism

O drug interactions are based on metabolic processes

O Pharmacists: To understand why certain drugs are contraindicated with other drugs

Drug Metabolism

PRODRUGS

O drugs biotransformed to pharmacologically active metabolites

O usually, parent compound is inactive when administered and must be metabolically converted to a biologically active drug

Drug Metabolism

Inactive Parent Compound Active Metabolite

O Sulindac (NSAID) O Sulfide Metabolite

Reduction

Drug Metabolism

Inactive Parent Compound Active Metabolite

O Azathioprine (Immunosuppresant)

O 6 – Mercapturine

Cleavage

Drug Metabolism

Inactive Parent Compound Active Metabolite

O Acyclovir (Antiviral) O Acyclovir triphosphate

Phosphorylation

Drug Metabolism

Active Parent Compound Active Metabolite

O Phenacetin (Analgesic)

O Acetaminophen

O-dealkylation

Drug Metabolism

Active Parent Compound Active Metabolite

O Imipramine

O Amitriptyline

(TCADs)

O Desipramine

O Nortriptyline

N-demethylation

Is drug metabolism a detoxification process?

Sites of Biotransformation

LIVERO most important organ in drug metabolism

INTESTINAL MUCOSAO important site of metabolism for orally

administered drugs

KIDNEYS, LUNGS, ADRENAL GLANDS, PLACENTA, BRAIN, SKINO substrate selective and more limited to

particular types of reaction

First Pass Effect

O phenomenon in drug metabolism whereby the concentration of drug is greatly reduced before it reaches the systemic circulation

O orally administered drugs that are absorbed into the bloodstream through the GI tract are susceptible for they must pass through the liver before further distributed into the system

Drugs Metabolized by the First Pass Effect

OLidocaine

OIsoproterenol

ONitroglycerin

OSalicylamide

OPropranolol

OPropoxyphene

OPentazocine

OMeperidine

OMorphine

Role of Enzymes in Biotransformation

Enzymes Reactions

Cytochrome P450s (CYP) C and O oxidation, dealkylation

Flavin-containing Monooxygenases (FMO)

N, S, and P oxidation

Epoxide hydrolases (mEHand sEH)

Hydrolysis of epoxides

Alcohol dehydrogenases Reduction of alcohols

Aldehyde dehydrogenases Reduction of aldehydes

Role of Enzymes in Biotransformation

Enzymes Reactions

Sulfotransferases (SULT) Addition of Sulfate

UDP-glucoronosyltransferases(UGT)

Addition of Glucoronic acid

Glutathione-S-transferases(UST)

Addition of Glutathione

N-acetyltransferases (NAT) Addition of Acetyl group

Methyltransferases (MT) Addition of Methyl group

Reaction Cycle involving Cytochrome p-450 in the oxidation of xenobiotics

Reaction Cycle involving Cytochrome p-450 in the oxidation of xenobiotics

Steps involved:

1. Drug substrate binds to CYP450

2. CYP450-Drug complex is reduced by NADPH

3. Molecular oxygen (O2) binds to the reduced CYP450-Drug complex

4. One atom of oxygen combines with the drug substrate, the other atom forms water

5. Oxygen is reduced to an “activated” state

6. The enzyme complex dissociates to yield free oxygenated drug metabolite

Pathways of Drug Metabolism

Phase I Reactions

O Oxidative reactions

O Reductive reactions

O Hydrolytic reactions

Phase II Reactions

O Glucuronic acid conjugation

O Sulfate conjugation

O Amino acid conjugation

O Glutathione or mercapturic acid conjugation

O Acetylation

O Methylation

Phase I Functionalization Reactions

O introduce functional polar groups (e.g., -OH, -COOH, -NH2, -SH) into the compound to produce a more water-soluble compound.

O may not produce sufficiently hydrophilic or inactive metabolites.

O the functional group on the molecule attached can undergo subsequent phase II reactions.

Phase I Functionalization Reactions

Direct Introduction of Functional Group

O Aromatic and Alipathic Hydroxylation

Phase I Functionalization Reactions

Modification of Existing Functionalities

O Reduction

RCOR/RCHO ROH (Alcohol)

azo/nitro groups RNH2 (Amine)

Phase I Functionalization Reactions

Modification of Existing Functionalities

O Oxidation

O ROH RCHO (Aldehyde)

O RCHO RCOOH (Carboxylic Acid)

O N, O, S -NH2, -OH, -SH

Phase I Functionalization Reactions

Modification of Existing Functionalities

O Hydrolysis

O esters/amides RCOOH

ROH RNH2

Phase II Conjugation Reactions

O attaches small, polar, and ionizableendogenous compounds (e.g. glucuronicacid, sulfate, glycine, and other amino acids) to the “handle” of phase I metabolites or parent compounds to form water-soluble CONJUGATED PRODUCTS – devoid of pharmacological activity

Phase II Conjugation Reactions

O Glucuronic acid conjugation

O Sulfate conjugation

O Amino acid conjugation (Glycine and Glutamine)

O Glutathione or mercapturic acid conjugation

O Acetylation

O Methylation

Pathways of Drug Metabolism

In Conclusion,

Phase I and II reactions complement one another in detoxifying and facilitating the elimination of drugs and xenobiotics.

e.g. Δ1 – tetrahydrocannabinol (principal psychoactive constituent of marijuana)

Pathways of Drug Metabolism

Refer to page 44of the book

Factors Affecting Drug Metabolism

Age DifferencesO oxidative and conjugative capabilities:

Newborn vs. Adult

Ooxidative metabolism of Tolbutamide is lower in newborns: t1/2 40 hrs; adults: t1/2 8 hrs

O inability of babies to glucuronidate Bilirubinleads to neonatal hyperbilirubinemia or Kernicterus

O inability of babies to conjugate Chloramphenicol results to Gray Baby Syndrome

Factors Affecting Drug Metabolism

Species and Strain Differences

O metabolism of drugs and foreign compounds is species dependent

O Amphetamine

O Humans, Rabbits, Guinea Pigs –

undergoes oxidative deamination

O Rats – undergoes aromatic hydroxylation

Factors Affecting Drug Metabolism

Species and Strain Differences

O Amphetamine

O Humans, Rabbits, Guinea Pigs – undergoes oxidative deamination

O Rats – undergoes aromatic hydroxylation

O Cats – poor glucuronidation; good sulfation

O Pigs – poor sulfation; poor glucuronidation

Factors Affecting Drug Metabolism

Species and Strain Differences

O even within the same species, individual variations (strain differences) may result in differences of specific metabolic pathways

O Acetylation

O Orientals and Eskimos – rapid acetylators

O Mediterrenean Jews and Egyptians – slowacetylators

Factors Affecting Drug Metabolism

Hereditary or Genetic Factors

O marked individual differences in the metabolism of several drugs exist in humans

Factors Affecting Drug Metabolism

Sex Differences

O species dependent

O significant in terms of drug-drug interactions based on the drug’s metabolism

O e.g. Aspirin and Nicotine are metabolized differently in men and women

Factors Affecting Drug Metabolism

Enzyme InductionO increased activity of drug metabolizing

enzymes

O increases the rate of drug metabolism and decreases the duration of drug action

O e.g. Phenobarbital and Warfarin: induction of phenobarbital increases the metabolism of warfarin which decreases the anticoagulant effect of the drug

Factors Affecting Drug Metabolism

Enzyme InhibitionO decreased activity of drug metabolizing

enzymes

O with decreased metabolism, the drug accumulates, leading to prolonged drug action and serious adverse effects

O e.g. grapefruit-drug interactions Carbamazepine (Tegretol), Atorvastatin(Lipitor), etc

Factors Affecting Drug Metabolism

Miscellaneous Factors

O Dietary Factors

O protein-carbohydrate ratio

O indoles present in vegetables

O polycyclic aromatic hydrocarbons in charcoal-broiled beef

O vitamins, minerals, starvation, malnutrition

Factors Affecting Drug Metabolism

Miscellaneous Factors

O Physiological Factors

O state of the liver

O pregnancy

O hormonal disturbances