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.