Pharmacokinetics and metabolism of sirolimus

Sirolimus (rapamycin, Rapamune) is a potent immunosuppressive drug that rec eived marketing approval from the US Food and Drug Administration on Septem ber 15, 1999. Research into defining its pharmacokinetic (PK) behavior, int eraction with other agents, and metabolism is ongoing. It has been establis hed that oral doses of both liquid and solid formulation are rapidly, thoug h incompletely and variably, absorbed. Metabolism by the intestinal and hep atic CYP3A family of enzymes likely contributes to variability in absorptio n and low bioavailability. Sirolimus has a long terminal half-life, the AUC correlates well with trough and peak concentrations, and it exhibits a mod erate degree of dose proportionality. There is significant interpatient var iability in PK parameters of sirolimus, though it exhibits predictable PK b ehavior when used with prednisone and cyclosporine neoral. There is a decre ased rejection risk with higher doses and target level attainment. Several species of sirolimus metabolites have been characterized, and are measurabl e in whole blood and tissue specimens. Many more species of sirolimus metab olites are detectable, but they are not quantifiable at this time. The tota l concentration of metabolites appears to be less than that of the parent d rug when examined through the PK profile. A reference method for the quanti tation of metabolites remains elusive because of a lack of proper standardi zation. The clinical significance of sirolimus metabolites remains to be pr oven.