Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
METABOLITE-P450 COMPLEX-FORMATION BY METHYLENEDIOXYPHENYL HIV PROTEASE INHIBITORS IN RAT AND HUMAN LIVER-MICROSOMES
Autore:
CHIBA M; NISHIME JA; CHEN IW; VASTAG KJ; SAHLY YS; KIM BM; DORSEY BD; VACCA JP; LIN JH;
Indirizzi:
MERCK SHARP & DOHME LTD,DEPT DRUG METAB,RES LABS W POINT PA 19486 MERCK SHARP & DOHME LTD,DEPT MED CHEM,RES LABS W POINT PA 19486
Titolo Testata:
Biochemical pharmacology
fascicolo: 2, volume: 56, anno: 1998,
pagine: 223 - 230
SICI:
0006-2952(1998)56:2<223:MCBMHP>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
CYTOCHROME-P450 3A4; OXIDATION; L-754,394; POTENT; PHARMACOKINETICS; INACTIVATION; DERIVATIVES; METABOLISM;
Keywords:
P450; CYP3A; CYP2D; MI COMPLEX;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
23
Recensione:
Indirizzi per estratti:
Citazione:
M. Chiba et al., "METABOLITE-P450 COMPLEX-FORMATION BY METHYLENEDIOXYPHENYL HIV PROTEASE INHIBITORS IN RAT AND HUMAN LIVER-MICROSOMES", Biochemical pharmacology, 56(2), 1998, pp. 223-230

Abstract

P450 complex formation and the unusual pharmacokinetics of methylenedioxyphenyl HIV protease inhibitors were examined by in vitro studies using human and rat liver microsomes and by in duo oral dosing studies. In vitro spectral studies indicated that the formation of a P450 complex having absorbance maxima at 425 and 456 nm was time and concentration dependent; 21-60% of the total P450 was complexed in dexamethasone-induced rat liver microsomes after a 30-min incubation with 100 mu M HIV protease inhibitors. Methoxy substitution on the phenyl ring of the methylenedioxyphenyl moiety increased formation of the P450 complex,whereas chlorine substitution markedly decreased the P450 complexation. Kinetic studies on the P450 complex formation indicated that both methoxy and chlorine substitution affected the maximum complex formation rate (V-max), while it had little effect on K-m values (similar to 10 mu M). This complexation in human liver microsomes was inhibited markedly by an anti-CYP3A1 antibody. Furthermore, the P450 complex formation resulted in a time-dependent loss of CYP3A-catalyzed marker activities (testosterone 2 beta/6 beta-hydroxylase) in both rat and human liver microsomes. Collectively, these results point to the involvement of CYP3A isoforms in P450 complexation by methylenedioxyphenyl HIV protease inhibitors. Additionally, after oral administration to rats, one of these HIV protease inhibitors (Compound I), which complexed P450 tothe greatest extent, showed no elimination over a period of 500 min after administration of the highest dose. It is suggested that formation of a quasi irreversible metabolite-CYP3A complex with methylenedioxyphenyl HIV protease inhibitors was responsible for the CYP3A-selectivetime-dependent loss of catalytic function and the unusual dose-dependent pharmacokinetics after oral administration. (C) Elsevier Science Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 24/01/20 alle ore 12:25:00