DRUG METABOLISM

ETATUTWUNI 0911013101

METABOLISM
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems.

Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products.

Biotransformation
Generates more polar (water soluble), inactive metabolites Readily excreted from body Metabolites may still have potent biological activity (or may have toxic properties) Generally applicable to metabolism of all xenobiotics as well as endogenous compounds such as steroids, vitamins and fatty acids

Sites of biotransformation
where ever appropriate enzymes occur; plasma, kidney, lung, gut wall and

LIVER
the liver is ideally placed to intercept natural ingested toxins (bypassed by injections etc) and has a major role in biotransformation

Phase I and Phase II Metabolism

Phase I
functionalization reactions

Phase II
conjugation reactions

Phase I
Converts the parent drug to a more polar metabolite by introducing or unmasking a functional group (-OH, -NH2, -SH). Usually results in loss of pharmacological activity Sometimes may be equally or more active than parent

Phase I Metabolism

Phase 1 metabolism is classified as the functionalization phase of drug metabolism; reactions carried out by phase 1 enzymes usually lead to the inactivation of an active drug. In certain instances, metabolism, usually the hydrolysis of an ester or amide linkage, results in bioactivation of a drug. Inactive drugs that undergo metabolism to an active drug are called prodrugs.

PHASE 1 reactions

Hydroxylation -CH2CH3 Oxidation -CH2OH

-CH2CH2OH -COOH - NHCH3 + CH3OH -CHCOCH3

+ NH3

-CHO

N-de-alkylation -N(CH3)2

Oxidative deamination -CH2CHCH3

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NH2

Prodrug
Pharmacologically inactive Converted rapidly to active metabolite (usually hydrolysis of ester or amide bond) Maximizes the amount of active species that reaches site of action

Phase II (conjugation reactions)

Subsequent reaction in which a covalent linkage is formed between a functional group on the parent compound or Phase I metabolite and an endogenous substrate such as glucuronic acid, sulfate, acetate, or an amino acid Highly polar rapidly excreted in urine and feces Usually inactive - notable exception is morphine 6-glucuronide

Phase II Metabolism
Phase II is usually the true detoxification of drugs Occurs mostly in cytosol Gives products that are generally water soluble and easily excreted Includes sugar conjugation, sulfation, methylation, acetylation, amino acid conjugation, glutathione conjugation

PHASE 2 reactions
(not all in liver) CONJUGATIONS
-OH, -SH, -COOH, -CONH with glucuronic acid to give glucuronides

-OH with sulphate to give sulphates

-NH2, -CONH2, aminoacids, sulpha drugs with acetyl- to give acetylated derivatives -halo, -nitrate, epoxide, sulphate with glutathione to give glutathione conjugates all tend to be less lipid soluble and therefore better excreted (less well reabsorbed)

Glucuronidation
Most widespread, important of the conjugation reactions Cofactor UDP glucuronic acid is in high abundance
Closely related to glycogen synthesis Found in all tissues of the body

Other sugars, glucose, xylose or ribose may be conjugated

Sulfation
Major conjugation pathway for phenols, also alcohols and amines Compounds that can be glucuronidated can also be sulfated Can be competition between the two pathways In general, sulfate conjugation predominates at low substrate concentration and glucuronide conjugation predominates at high substrate concentration

Glutathione Conjugation
Glutathione is a protective compound (tripeptide, GlyCys-Glu) within the body for removal of potentially toxic electrophilic compounds Many drugs are, or are metabolized in phase I to, strong electrophiles React with glutathione to form non- toxic conjugates Glutathione conjugates may be excreted directly in urine or bile, but are usually metabolized further

Stereoselective Reactions
Many drugs in use are optically active Optical isomers of many drugs are metabolized differently Warfarin exists as R- and S-isomers, the S isomer disappears from the plasma at a faster rate than the R isomer

Site of Biotransformation
Enzymatic in nature Enzyme systems involved are localized in liver Every tissue has some metabolic activity Other organs with significant metabolic capacity are gi tract, kidneys and lung

First-Pass Metabolism
Following nonparenteral administration of a drug, a significant portion of the dose may be metabolically inactivated in either the intestinal endothelium or the liver before it reaches the systemic circulation Limits oral availability of highly metabolized drugs

Endoplasmic Reticulum (microsomal) and Cytosol

With respect to drug metabolizing reactions, two sub cellular organelles are quantitatively the most important: the endoplasmic reticulum and the cytosol. The phase I oxidative enzymes are almost exclusively localized in the endoplasmic reticulum. Phase II enzymes are located predominantly in the cytosol.

Cytochrome P450 Monooxygenase System

Superfamily of heme containing proteins Involved in metabolism of diverse endogenous and exogenous compounds
Drugs Environmental chemicals Other xenobiotics

Factors affecting Drug Metabolism

Genetic Variation Physiologic Condition Disease Factors Environmental Determinants Induction Inhibition

GENETICS VARIATION

Genetic different within population. Racial differences among different populations.

PHYSIOLOGIC CONDITIONS
Age reduced in aged patients & children Gender women slower ethanol metabilizers Diet/Nutrition Pathophysiology

Disease Factors
Liver Disease Cirrhosis, Alcoholic liver disease, jaundice, carcinoma Major location of drug metabolizing enzymes Dysfunction can lead to impaired drug metabolismdecreased enzyme activity First pass metabolism effected may inc 2-4 x bioavailiability Results in exaggerated pharmacological responses and adverse effects Cardiac failure causes decreased blood flow to the liver Hormonal diseases, infections and inflammation can change drug metabolizing capacity

Environmental Determinants
Activity of most drug metabolizing enzymes can be modulated by exposure to certain exogenous compounds Drugs Dietary micronutrient (food additives, nutritional or preservative) Environmental factors (pesticides, industrial chemicals) Can be in the form of induction or inhibition Contributes to interindividual variability in the metabolism of many drugs

ENVIRONMENTAL FACTORS
1. Enzyme induction A drug or chemical-stimulated increase in enzyme activity usually due to an increase in the amount of enzyme present. Examples: Rifampicin Phenobarbital Carbamazepine Benzopyren (Smoking) Chlordane (Insecticide)

2. Enzyme inhibition May be due to substrate competition or due to direct inhibition of drug metabolizing enzyme, particularly one of several of the cytochrome P-450 enzymes. Examples: Fluoxetine decrease the clearance of IMI due to its inhibitory effect of hydroxylation.