Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery.

The objective of this section is to evaluate the contributions of hepatic metabolism, intestinal metabolism and intestinal p-glycoprotein to the pharmacokinetics of orally administered cyclosporine and tacrolimus. Cyclosporine and tacrolimus are metabolized primarily by cytochrome P450 3A4 (CYP3A4) in the liver and small intestine. There is also evidence that cyclosporine is metabolized to a lesser extent by cytochrome P450 3A5 (CYP3A5). Cyclosporine and tacrolimus are also substrates for p-glycoprotein, which acts as a counter-transport pump, actively transporting cyclosporine and tacrolimus back into the intestinal lumen. Traditional teaching of clinical drug metabolism has been that hepatic metabolism is of primary importance, and other sites of metabolism play a relatively minor role. It appears as though intestinal metabolism plays a much greater role in the pharmacokinetics of orally administered drugs than previously thought. Intestinal metabolism may account for as much as 50% of oral cyclosporine metabolism. There are at least two components of intestinal metabolism for cyclosporine and tacrolimus, 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 cyclosporine pharmacokinetics in kidney transplant patients. However, the quantity of intestinal p-glycoprotein accounts for approximately 17% of the variability in oral cyclosporine pharmacokinetics. It may be that p-glycoprotein maximizes drug exposure to intestinal enzymes, thus decreasing the importance of enzyme quantity. Since cyclosporine's FDA approval in 1983, there have been many reports of clinically significant drug interactions of other agents when given concomitantly with cyclosporine. With the FDA approval of tacrolimus in 1994, a similar pattern of clinically significant drug interactions appears to be emerging. It seems that compounds that alter (either induce or inhibit) CYP3A4 and/or p-glycoprotein will alter the oral pharmacokinetics of cyclosporine and tacrolimus. It should be expected that, until further data are available, the drugs which interact with cyclosporine will also interact with tacrolimus.