RESUMO
PURPOSE: The expression of cytochrome P450 enzymes (CYPs) in animals and humans is under complex hormonal regulation. Chronic treatment with drugs that alter sex hormone levels such as GnRH receptor agonists or antagonists may affect the expression of hormone-dependent CYPs, and as a result the pharmacokinetics of drugs metabolized by them. METHODS: Enzyme kinetic parameters were obtained by incubating AG-045572 (0.1-30 microM) with human or rat liver microsomes, or expressed CYP3A4 and CYP3A5. The pharmacokinetics of AG-045572 (10 mg/kg i.v. or 20 mg/kg p.o.) were studied in intact male, female, castrated male and male rats pretreated with AG-045572 for 4 days. RESULTS: AG-045572 is metabolized by CYP3A in both rats and humans. The Km values were similar in male and female human, female rat liver microsomes, and expressed CYP3A4 and CYP3A5 (0.39, 0.27, 0.28, 0.25, and 0.26 microM, respectively). The Km in male rat liver microsomes was 1.5 microM, suggesting that in male and female rats AG-045572 is metabolized by different CYP3A isozymes. The oral bioavailability of AG-045572 in intact male rats was 8%, while in female or castrated male rats it was 24%. Pretreatment of intact male rats with AG-045572 i.m. for 4 days resulted in suppression of testosterone to castrate levels, accompanied by an increase in oral bioavailability of AG-045572 to 27%. In the same experiment, the male-specific pulsatile pattern of growth hormone remained unchanged with slightly elevated baseline levels. CONCLUSIONS: The potent GnRH receptor antagonist AG-045572 is metabolized by hormone-dependent CYP3A. As a result, suppression of testosterone by pretreatment with AG-045572 "feminized" its own pharmacokinetics.
Assuntos
Hidrocarboneto de Aril Hidroxilases , Furanos/farmacologia , Antagonistas de Hormônios/farmacocinética , Receptores LHRH/antagonistas & inibidores , Testosterona/antagonistas & inibidores , Tetra-Hidronaftalenos/farmacologia , Algoritmos , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Feminino , Hormônio do Crescimento/sangue , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Oxirredutases N-Desmetilantes/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Testosterona/sangueRESUMO
A series of alkylidene hydrazide derivatives containing an alkoxyaryl moiety was optimized. The resulting hydrazide-ethers were competitive antagonists at the human glucagon receptor. Pharmacokinetic experiments showed fast clearance of most of the compounds tested. A representative compound [4-hydroxy-3-cyanobenzoic acid (4-isopropylbenzyloxy-3,5-dimethoxymethylene)hydrazide] with an IC50 value of 20 nM was shown to reduce blood glucose levels in fasted rats.