SPECIES-DIFFERENCES IN THE METABOLISM OF A POTENT HIV-1 REVERSE-TRANSCRIPTASE INHIBITOR L-738,372 - IN-VIVO AND IN-VITRO STUDIES IN RATS, DOGS, MONKEYS, AND HUMANS

In vivo and in vitro metabolism of dihydro-4-((2-pyridyl)ethynyl)quina zolin-2(1H)-one (L-738,372), a potent human immunodeficiency virus-typ e 1 reverse transcriptase inhibitor, has been investigated in rats, do gs, and monkeys. Following 0.9 mg/kg iv and 9 mg/kg po doses, systemic blood clearance (CL,) and bioavailability (F) of L-738,372 were speci es-dependent and inversely related (CL(B) = 48, 15, and 3 ml/min/kg; F = 6, 62, and 94%, in dogs, rats, and monkeys, respectively). Incubati on of L-738,372 with rat liver slices and liver microsomes from all sp ecies studied led to the formation of two hydroxylated metabolites, M1 and M2. Kinetic studies of the microsomal metabolism of L-738,372 ind icated that M1 was formed by a much higher affinity, but lower capacit y enzyme(s) than that which catalyzed M2 formation in rats, dogs, and monkeys. The total intrinsic clearance of metabolite formation (CL(int ) total = CL(int) M1 + CL(int) M2) was highest in dogs, followed by ra ts and monkeys. In dogs, CL,, total was caused almost exclusively by C L(int) M1. Extrapolation of the CL(int) total values to the hepatic cl earances (19, 8.4, and 0.9 ml/min/kg in dogs, rats, and monkeys, respe ctively) showed a similar rank order to the CL(B) observed in vivo. Go od agreement between these in vivo and in vitro results suggests that the species differences in hepatic first-pass metabolism, and not the intrinsic absorption, contributed significantly to the observed differ ences in F. Similar to the results observed with monkey liver preparat ions, human liver microsomes metabolized L-738,372 poorly, suggesting the possibility of low metabolic clearance and high F of L-738,372 in humans. In rats, the hepatic formation of M1 and M2 was gender-depende nt and affected differentially by various P450 inducers. Female rats g enerated M1 and M2 much more slowly than male rats. Dexamethasone (DX) and phenobarbital (PB), but not 3-methylcholanthrene (3-MC), signific antly increased the formation rate of M2. M1 formation was markedly de creased by PB, but unaffected by DX and 3-MC. Pretreatment of rats wit h L-738,372 (200 mg/kg po for 4 days) decreased the formation of M1, b ut increased that of M2, resulting in a decreased CL(int) total. Immun oblot analysis revealed induction of hepatic cytochrome P4503A, 2B1/2, and 2C6 by L-738,372 pretreatment, but indicated suppression of cytoc hrome P4502C11. Collectively, these data suggested 1) a potentially de creased systemic clearance, and consequently increased F of L-738,372 during multiple-dose therapy, and 2) a possible involvement of cytochr ome P4503A and cytochrome P4502C11 in the formation of M2 and M1, resp ectively, in the rat.