DISPOSITION OF L-732,531, A POTENT IMMUNOSUPPRESSANT, IN RATS AND BABOONS

L-732,531 is a semi-synthetic analog of the macrolide tacrolimus (Prog raf(R)). Like tacrolimus, L-732,531 is a potent immunosuppressant. In this study, its absorption, distribution, metabolism, and excretion we re studied in rats and baboons. In rats, its blood and plasma levels w ere similar, whereas in baboons, its blood levels were, on average, tw ice as high as those in plasma. This was consistent with the in vitro blood-to-plasma ratio of L-732,531, which in these two species, as wel l as in humans, was much lower than that of tacrolimus and showed a mi nimal concentration dependence. After iv administration to rats, the b lood and plasma clearance of L-732,531 decreased from similar to 60 ml /min/kg at 0.2 mg/kg to 30 ml/min/kg when dosed at 1 and 3 mg/kg. Afte r oral administration, plasma area under the concentration vs, time cu rve (AUC) and maximal plasma concentration (C-max) increased more than proportionally to the dose. At 1, 5, and 15 mg/kg, plasma AUC was 29, 466, and 2832 ng.hr/ml, respectively, and C-max was 10, 129, and 304 ng/ml, respectively. Bioavailability, although compromised by nonlinea r kinetics, was estimated to be between 8% and 18%. In baboons, the cl earance of L-732,531 was lower than that in rats, especially when calc ulated from blood concentrations (12 ml/min/kg at 0.2 mg/kg and 8 ml/m in/kg at 1 mg/kg). After oral dosing, baboon plasma AUC and C-max were much lower than those in rats, but as in rats, they increased more th an proportionally with increasing doses. The bioavailability of L-732, 531 in baboons was estimated at 3%, 9%, and 24% when animals were dose d at 5, 15, and 26 mg/kg pc, respectively. After oral administration o f [H-3]L-732,531 at 5 mg/kg, similar to 32% of the radioactivity was r ecovered in bile and urine of rats, compared with 9% in baboons. High- performance liquid chromatography profiles of rat and baboon plasma, b ile, urine, and feces indicated that L-732,531 was metabolized extensi vely to a complex mixture of products. Some intact parent drug was obs erved in feces of orally dosed animals, indicating incomplete absorpti on. In vitro, L-732,531 was metabolized more extensively by baboon liv er microsomes than rat or human microsomes. Its metabolism in human li ver microsomes was shown to be catalyzed primarily by cytochrome P450 3A isozymes.