title: 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.
abstract: 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)
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: T
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: S K
authors.initials: SK
authors.lastname: Balani
authors.forename: L M
authors.initials: LM
authors.lastname: Dwyer
authors.forename: J D
authors.initials: JD
authors.lastname: Ellis
authors.forename: L R
authors.initials: LR
authors.lastname: Kauffman
authors.forename: S L
authors.initials: SL
authors.lastname: Varga
authors.forename: S M
authors.initials: SM
authors.lastname: Pitzenberger
authors.forename: A D
authors.initials: AD
authors.lastname: Theoharides
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D054303:HIV Reverse Transcriptase; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D011799:Quinazolines / Q000378:metabolism* / Q000493:pharmacokinetics; D052999:Quinazolinones; D012194:RNA-Directed DNA Polymerase / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D012737:Sex Factors; D013045:Species Specificity
chemical_list: D000998:Antiviral Agents; D011799:Quinazolines; D052999:Quinazolinones; D018894:Reverse Transcriptase Inhibitors; C091038:L 738372; D003577:Cytochrome P-450 Enzyme System; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase