L-738372

In vivo and in vitro metabolism of 6-chloro-4(S)-cyclopropyl-3,4-dihydro-4-((2-pyridyl)ethynyl)quinazolin-2(1H)-one (L-738,372), a potent human immunodeficiency virus-type 1 reverse transcriptase inhibitor, has been investigated in rats, dogs, and monkeys.Following 0.9 mg/kg i.v. and 9 mg/kg po doses, systemic blood clearance (CL_B) and bioavailability (F) of L-738,372 were species-dependent and inversely related (CL_B = 48, 15, and 3 mL/min/kg; F = 6, 62, and 94%, in dogs, rats, and monkeys, resp.).Incubation of L-738,372 with rat liver slices and liver microsomes from all species studied led to the formation of two hydroxylated metabolites, M1 and M2.Kinetic studies of the microsomal metabolism of L-738,372 indicated that M1 was formed by a much higher affinity, but lower capacity 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 rats and monkeys.In dogs, CL_int total was caused almost exclusively by CL_int M1.Extrapolation of the CL_int total values to the hepatic clearances (19, 8.4, and 0.9 mL/min/kg in dogs, rats, and monkeys, resp.) showed a similar rank order to the CL_B observed in vivo.Good 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 differences in F.Similar to the results observed with monkey liver preparations, 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-dependent and affected differentially by various P 450 inducers.Female rats generated M1 and M2 much more slowly than male rats.Dexamethasone (DX) and phenobarbital (PB), but not 3-methylchloranthrene (3-MC), significantly increased the formation rate of M2.M1 formation was markedly decreased by PB, but unaffected by DX and 3-MC.Pretreatment of rats with L-738,372 (200 mg/kg po for 4 days) decreased the formation of M1, but increased that of M2, resulting in a decreased CL_int total.Immunoblot anal. revealed induction of hepatic cytochrome P 4503A, 2B1/2, and 2C6 by L-738,372 pretreatment, but indicated suppression of cytochrome P 4502C11.Collectively, these data suggested (1) a potentially decreased systemic clearance, and consequently, increased F of L-738,372 during multiple-dose therapy, and (2) a possible involvement of cytochrome P 4503A and cytochrome P 4502C11 in the formation of M2 and M1, resp., in the rat.

In vivo and in vitro metabolism of 6-chloro-4(S)-cyclopropyl-3,4-dihydro-4-((2-pyridyl) ethynyl)quinazolin-2(1H)-one (L-738,372), a potent human immunodeficiency virus-type 1 reverse transcriptase inhibitor, has been investigated in rats, dogs, and monkeys. Following 0.9 mg/kg iv and 9 mg/kg po doses, systemic blood clearance (CLB) and bioavailability (F) of L-738,372 were species-dependent and inversely related (CLB = 48, 15, and 3 ml/min/kg; F = 6, 62 and 94%, in dogs, rats, and monkeys, respectively). Incubation of L-738,372 with rat liver slices and liver microsomes from all species studied led to the formation of two hydroxylated metabolites, M1 and M2. Kinetic studies of the microsomal metabolism of L-738,372 indicated that M1 was formed by a much higher affinity, but lower capacity 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 rats and monkeys. In dogs, CL(int) total was caused almost exclusively by CL(int) M1. Extrapolation of the CL(int) total values to the hepatic clearances (19, 8.4, and 0.9ml/min/kg in dogs, rats, and monkeys, respectively) showed a similar rank order to the CLB observed in vivo. Good 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 differences in F.(ABSTRACT TRUNCATED AT 250 WORDS)