Renal excretion plays a pivotal role in terminating the biologic activity of a few drugs, particularly those that have small molecular volumes or possess polar characteristics such as functional groups fully ionized at physiologic pH.

Pharmacologically active organic molecules tend to be lipophilic and remain unionized or only partially ionized at physiologic pH. They are often strongly bound to plasma proteins. Such substances are not readily filtered at the glomerulus. The lipophilic nature of renal tubular membranes also facilitates the reabsorption of hydrophobic compounds following their glomerular filtration.

Consequently, most drugs would have a prolonged duration of action if termination of their action depended solely on renal excretion. An alternative process that may lead to the termination or alteration of biologic activity is metabolism. In general, lipophilic xenobiotics are transformed to more polar and hence more readily excretable products.

Metabolic products are often less active than the parent drug and may even be inactive. However, some biotransformation products have enhanced activity or toxic properties, including mutagenicity (induce heritable alteration of DNA), teratogenicity (production of birth defects), and carcinogenicity (cause cellular transformation). This observation undermines the once popular theory that drug-biotransforming enzymes evolved as a biochemical defense mechanism for the detoxification of environmental xenobiotics.

The synthesis of endogenous substrates such as steroid hormones, cholesterol, and bile acids involves many enzyme-catalyzed pathways associated with the metabolism of xenobiotics. The same is true of the formation and excretion of endogenous metabolic products such as bilirubin, the end catabolite of heme.

Finally, drug-metabolizing enzymes have been exploited through the design of pharmacologically inactive pro-drugs that are converted in vivo to pharmacologically active molecules.