Metabolism of Drugs

Drug metabolism has five possible consequences of therapeutic significance. With many exceptions, the primary purpose of metabolism is to change lipid soluble active compounds (which are not readily eliminated from the body) to water soluble inactive compounds that can easily be excreted. Metabolites are usually less lipid soluble and less active than the parent compound. However, many drug metabolites have pharmacological activity or, occasionally, are more toxic than the parent compound (e.g., acetaminophen). Some drugs may be "prodrugs", which must be metabolized to active compounds (many of the ACE inhibitors, e.g., lisinopril, are prodrugs).

The rate of drug metabolism differs markedly among races as well as individuals. Infants & elderly often having decreased drug metabolizing capabilities.

Pharmacogenetics is a consideration of increasing importance in determining drug effect in certain individuals.

Pattern of biotransformation

a. Reactions are classified as phase I and phase II

ACTIVE DRUG ≫ PHASE I(ASYNTHETIC)≫OXIDIZED PRODUCT≫ PHASE II (SYNTHETIC)≫CONJUGATED PRODUCT(INACTIVE)

b. Phase I (termed "asynthetic") usually converts the parent drug to more polar metabolites by oxidation, reduction, hydrolysis, dealkylation, etc. Phase I products may or may not be active.

c. Phase II ("synthetic") involves coupling the drug or its phase I metabolite to endogenous water-soluble substrates, such as glucuronic acid, sulfuric acid, mercapturic acid, acetic acid, or amino acid. Phase II products are usually inactive. All conjugation reactions except glucuronidation are catalyzed by nonmicrosomal enzymes.

d. Drug metabolism may take place in any portion or organ of the body although hepatic microsomal enzyme systems are responsible for the biotransformation of the majority of drugs. Plasma, kidney, lung, and GI tract also contain enzymes that contribute to drug metabolism.

Category: Pharmacology Notes