| Drugs and foreign chemicals that are lipid soluble are converted by enzymatic processes to compounds of ever-increasing water-solubility until they can be excreted via one or several of the routes available. Metabolism or biotransformation and the subsequent excretion of drugs is known as “elimination.” Metabolism generally occurs in 2 phases: Phase I induces a chemical change (most frequently oxidation, but also reduction) that renders the drug more conducive to phase II. Phase II
is a conjugative or synthetic addition of a large, polar molecule that renders the drug water soluble and amenable to renal excretion. |
| There are several possible consequences of the biochemical transformation of drugs: 1) inactivation, during which an active drug is converted to inactive metabolite(s); 2) activation, during which an inactive drug (or pro-drug) is converted to a pharmacologically active primary metabolite; 3) modification of activity after the conversion of an active drug to a metabolite that also has pharmacologic activity; 4) lethal synthesis (or intoxication), in which a drug is incorporated
into a normal cellular metabolic pathway that ultimately leads to failure of the reaction sequence because of the presence of spurious substrate (cell death then occurs). |
| Several aspects of the biotransformation of drugs have direct clinical significance. These include microsomal enzyme induction and inhibition, nutritional state, age, disease conditions, and species differences. |
| Because drug biotransformation is negligible in early life, neonates are much more sensitive to lipid-soluble drugs than are adults of any species. The postnatal development of drug-metabolizing enzymes in the liver appears to be biphasic, consisting of a rapid and nearly linear increase in activity during the first 3-4 wk, followed by slower development up to the tenth week postpartum; dose or interval for the very young must be reduced accordingly. Hepatic mass, hepatic blood
flow, and microsomal enzyme activity may decrease in older animals. |
| Many disease states impair the normal activity of the hepatic microsomal enzyme system, which in turn prolongs the half-lives of many drugs. Frank hepatotoxicity, acute hepatitis, or other extensive liver lesions invariably depress enzyme activity. Changes in hepatic blood flow, with similar consequences, may be encountered in congestive heart failure, circulatory shock, and cirrhosis. Hypothyroidism tends to reduce microsomal enzyme function, and hyperthyroidism tends to increase activity. |
| Species variations in the biotransformation patterns of lipid-soluble drugs are common. Differences in the duration of action of these drugs in various species frequently can be attributed to differences in their rates of biotransformation. This must be remembered when either dosages or withdrawal times are extrapolated from one species to another. |
