RT Journal Article
SR Electronic
T1 Disposition of L-732,531, a Potent Immunosuppressant, in Rats and Baboons
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 949
OP 957
VO 26
IS 10
A1 B. V. Karanam
A1 R. R. Miller
A1 A. Colletti
A1 T. Montgomery
A1 K. D. Carey
A1 T. Hawkins
A1 Y. S. Tang
A1 M. Lavin
A1 R. A. Stearns
A1 S. H. L. Chiu
A1 S. H. Vincent
YR 1998
UL http://dmd.aspetjournals.org/content/26/10/949.abstract
AB L-732,531 is a semi-synthetic analog of the macrolide tacrolimus (Prograf®). Like tacrolimus, L-732,531 is a potent immunosuppressant. In this study, its absorption, distribution, metabolism, and excretion were studied in rats and baboons. In rats, its blood and plasma levels were similar, whereas in baboons, its blood levels were, on average, twice 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 well as in humans, was much lower than that of tacrolimus and showed a minimal concentration dependence. After iv administration to rats, the blood and plasma clearance of L-732,531 decreased from ∼60 ml/min/kg at 0.2 mg/kg to 30 ml/min/kg when dosed at 1 and 3 mg/kg. After oral administration, plasma area under the concentration vs. time curve (AUC) and maximal plasma concentration (Cmax) 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, andCmax was 10, 129, and 304 ng/ml, respectively. Bioavailability, although compromised by nonlinear kinetics, was estimated to be between 8% and 18%. In baboons, the clearance of L-732,531 was lower than that in rats, especially when calculated from blood concentrations (12 ml/min/kg at 0.2 mg/kg and 8 ml/min/kg at 1 mg/kg). After oral dosing, baboon plasma AUC andCmax were much lower than those in rats, but as in rats, they increased more than proportionally with increasing doses. The bioavailability of L-732,531 in baboons was estimated at 3%, 9%, and 24% when animals were dosed at 5, 15, and 26 mg/kg po, respectively. After oral administration of [3H]L-732,531 at 5 mg/kg, ∼32% of the radioactivity was recovered in bile and urine of rats, compared with 9% in baboons. High-performance liquid chromatography profiles of rat and baboon plasma, bile, urine, and feces indicated that L-732,531 was metabolized extensively to a complex mixture of products. Some intact parent drug was observed in feces of orally dosed animals, indicating incomplete absorption. In vitro, L-732,531 was metabolized more extensively by baboon liver microsomes than rat or human microsomes. Its metabolism in human liver microsomes was shown to be catalyzed primarily by cytochrome P450 3A isozymes. The American Society for Pharmacology and Experimental Therapeutics