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Titolo:
Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport
Autore:
Katoh, M; Nakajima, M; Yamazaki, H; Yokoi, T;
Indirizzi:
Kanazawa Univ, Fac Pharmaceut Sci, Div Drug Metab, Kanazawa, Ishikawa 9200934, Japan Kanazawa Univ Kanazawa Ishikawa Japan 9200934 wa, Ishikawa 9200934, Japan
Titolo Testata:
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
fascicolo: 4, volume: 12, anno: 2001,
pagine: 505 - 513
SICI:
0928-0987(200102)12:4<505:IEOCSA>2.0.ZU;2-N
Fonte:
ISI
Lingua:
ENG
Soggetto:
DRUG-METABOLISM; CYTOCHROME-P-450 ENZYMES; MULTIDRUG-RESISTANCE; LIVER-MICROSOMES; CYCLOSPORINE-A; CACO-2 CELLS; AZELASTINE; AMIODARONE; ABSORPTION; OXIDATION;
Keywords:
CYP3A4; metabolism; P-glycoprotein; transport; drug interactions;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
33
Recensione:
Indirizzi per estratti:
Indirizzo: Yokoi, T Kanazawa Univ, Fac Pharmaceut Sci, Div Drug Metab, Takara Machi 13-1, Kanazawa, Ishikawa 9200934, Japan Kanazawa Univ Takara Machi 13-1 Kanazawa Ishikawa Japan 9200934 n
Citazione:
M. Katoh et al., "Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport", EUR J PH SC, 12(4), 2001, pp. 505-513

Abstract

It is generally known that the substrates and/or inhibitors of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) overlap with each other. In intestinal epithelial cells, it is surmised that the metabolites coexist with their parent drug. However, most studies on P-gp did not take the effects of those metabolites into consideration. Therefore, in the present study, we investigated the inhibitory effects of five substrates of CYP3A4 (nifedipine,testosterone, midazolam, amiodarone, and azelastine) and their metaboliteson the P-gp-mediated transcellular transport. The transcellular transportsof [H-3]daunorubicin or [H-3]digoxin by monolayers of LLC-GA5-COL150 cellsin which P-gp was overexpressed were measured in the presence or absence of the CYP3A4 substrates and their metabolites. Nifedipine, testosterone, midazolam, and their metabolites exhibited no effects on the P-gp-mediated transport of [H-3]daunorubicin and [H-3]digoxin. On the other hand, the transport of [3H]daunorubicin was strongly inhibited by amiodarone, desethylamiodarone, azelastine, and desmethylazelastine, with IC50 values of 22.5, 15.4, 16.0 and 11.8 muM, respectively. The transport of [H-3]digoxin was also strongly inhibited by these compounds, with IC50 values of 45.6, 25.2, 30.0 and 41.8 muM, respectively. Another metabolite of azelastine, 6-hydroxyazelastine, exhibited no effects on these transports. It was suggested that theCYP3A4 metabolites of which their parent drug exhibited inhibition on the P-gp-mediated transport are possibly also inhibitors. It would be possible more complicated drug-drug interactions would be caused by the metabolites as well as their parent drugs in the liver and the intestine via the inhibition of CYP3A4 and P-gp. (C) 2001 Elsevier Science B.V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/04/20 alle ore 04:05:28