Drug metabolism by cytochromes P450 in the liver and small bowel.

Most drugs used clinically are metabolized by cytochromes P450. These enzymes have been best characterized in the liver, where it appears the major drug-metabolizing P450s belong to three gene families. There appear to be remarkable differences among patients in the catalytic activity of each of the P450s within these three families, and it is increasingly evident that this heterogeneity accounts, at least in part, for differences among patients in response to many medications. In addition, it is clear that many important drug interactions result from induction or inhibition, or both, of the catalytic activity of P450s. Many interactions involving P450s can be reproduced in liver microsomes or in cultured hepatocytes, and it is likely that such studies will, in the future, alert physicians to potential drug interactions before they are reported. Finally, mounting evidence shows that many of the clinically relevant aspects of P450s that have been ascribed to the liver may in fact be occurring at the level of the intestinal mucosa. This finding has been demonstrated most clearly with CsA and P450IIIA, in which enterocyte metabolism appears largely to account for drug interactions and differences among patients in dosing requirements. It remains to be determined whether other enterocyte P450s are also clinically important.