CONTRIBUTIONS OF HEPATIC AND INTESTINAL METABOLISM AND P-GLYCOPROTEINTO CYCLOSPORINE AND TACROLIMUS ORAL-DRUG DELIVERY

The objective of this section is to evaluate the contributions of hepa tic metabolism, intestinal metabolism and intestinal p-glycoprotein to the pharmacokinetics of orally administered cyclosporine and tacrolim us. Cyclosporine and tacrolimus are metabolized primarily by cytochrom e P450 3A4 (CYP3A4) in the liver and small intestine. There is also ev idence that cyclosporine is metabolized to a lesser extent by cytochro me P450 3A5 (CYP3A5). Cyclosporine and tacrolimus are also substrates for p-glycoprotein, which acts as a counter-transport pump, actively t ransporting cyclosporine and tacrolimus back into the intestinal lumen . Traditional teaching of clinical drug metabolism has been that hepat ic metabolism is of primary importance, and other sites of metabolism play a relatively minor role. It appears as though intestinal metaboli sm plays a much greater role in the pharmacokinetics of orally adminis tered drugs than previously thought. Intestinal metabolism may account for as much as 50% of oral cyclosporine metabolism. There are at leas t two components of intestinal metabolism for cyclosporine and tacroli mus, intestinal CYP3A4/CYP3A5 and intestinal p-glycoprotein activities . The quantity of intestinal enzymes, although highly variable, do not appear to be the key to explaining the variability of oral cyclospori ne pharmacokinetics in kidney transplant patients. However, the quanti ty of intestinal p-glycoprotein accounts for approximately 17% of the variability in oral cyclosporine pharmacokinetics. It may be that p-gl ycoprotein maximizes drug exposure to intestinal enzymes, thus decreas ing the importance of enzyme quantity. Since cyclosporine's FDA approv al in 1983, there have been many reports of clinically significant dru g interactions of other agents when given concomitantly with cyclospor ine. With the FDA approval of tacrolimus in 1994, a similar pattern of clinically significant drug interactions appears to be emerging. It s eems that compounds that alter (either induce or inhibit) CYP3A4 and/o r p-glycoprotein will alter the oral pharmacokinetics of cyclosporine and tacrolimus. It should be expected that, until further data are ava ilable, the drugs which interact with cyclosporine will also interact with tacrolimus. (C) 1997 Elsevier Science B.V.