       Document 0672
 DOCN  M9620672
 TI    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 human.
 DT    9602
 AU    Prueksaritanont T; Balani SK; Dwyer LM; Ellis JD; Kauffman LR; Varga SL;
       Pitzenberger SM; Theoharides AD; Department of Drug Metabolism, Merck
       Research Laboratories, West; Point, PA 19486, USA.
 SO    Drug Metab Dispos. 1995 Jul;23(7):688-95. Unique Identifier : AIDSLINE
       MED/96089969
 AB    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)
 DE    Animal  Antiviral Agents/*METABOLISM/PHARMACOKINETICS  Comparative Study
       Cytochrome P-450/BIOSYNTHESIS  Dogs  Dose-Response Relationship, Drug
       Enzyme Induction/DRUG EFFECTS  Female  Human  Kinetics
       Liver/ENZYMOLOGY/METABOLISM  Male  Microsomes,
       Liver/ENZYMOLOGY/METABOLISM  Quinazolines/*METABOLISM/PHARMACOKINETICS
       Rats  Rats, Sprague-Dawley  Reverse Transcriptase
       Inhibitors/*METABOLISM/PHARMACOKINETICS  RNA-Directed DNA
       Polymerase/DRUG EFFECTS  Sex Factors  Species Specificity  JOURNAL
       ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

