Extrahepatic metabolism of drugs in humans.

Although the liver plays the major role in drug metabolism [e.g. by oxidative cytochrome P450 (CYP)-dependent phase I and conjugation or phase II reactions], drug metabolising enzymes are also present at other sites. Depending on the particular drug and enzymes involved, these extrahepatic organs and/or tissues can contribute to the elimination of drugs and, thus, should be considered in any discussion of drug disposition. By the use of relatively new techniques in molecular biology, e.g. immunoblotting with antibodies directed to various CYP isoenzymes, the tissue and organ distribution of these drug metabolising enzymes can be determined. In addition, microsomal and cytosolic enzyme activity and capacity can be directly assessed in vitro by incubation of the enzymes with the drugs of interest. Both approaches have demonstrated the presence of 3 CYP families at different extrahepatic sites, such as the mucosa of the gastrointestinal tract, kidney, lung, brain or skin. Enzymes including epoxide hydrolases, hydrolysing enzymes, glutathione S-transferases, UDP-glucuronosyltransferases, sulphotransferases, N-acetyltransferases, and methyltransferases are discussed. Indirect evidence of extrahepatic drug metabolism can be generated from pharmacokinetic studies whenever total body clearance exceeds liver blood flow, or when severe liver dysfunction or anhepatic conditions do not affect metabolic clearance. Indeed, extrahepatic metabolism has been demonstrated for numerous drugs. Therefore, the metabolic profile and sites of enzymatic reactions for each drug should be determined.