SPECIES-DIFFERENCES IN SIROLIMUS STABILITY IN HUMANS, RABBITS, AND RATS

Species differences in the in vitro stability of sirolimus was assesse d in plasma and whole blood in relation to red blood cell distribution , Fresh blood and plasma samples obtained from humans, rabbits, and ra ts were aliquoted and spiked with sirolimus, After incubation from 0 t o 144 hr in a shaking water bath maintained at 37 degrees C, sirolimus concentrations were quantified by a specific high-liquid performance chromatographic method. Sirolimus was unstable in both plasma and whol e blood, Sirolimus degradation half-life in whole blood was 135 hr (vs , 7.2 hr in plasma) in humans, 62 hr (vs, 3.1 hr) in rabbits, and 15 h r (vs. 2.2 hr) in rats, Sirolimus stability is greater in whole blood compared with plasma in proportion to the whole blood/plasma ratio and hematocrit, In vivo instability may account for up to 36% of sirolimu s clearance in humans and 13% in rabbits, and this is an important fac tor in the pharmacokinetics of this drug.