The utility of in vitro data in making accurate predictions of human P-glycoprotein-mediated drug-drug interactions: a case study for AZD5672.
Drug Metab Dispos
; 39(2): 275-82, 2011 Feb.
Article
em En
| MEDLINE
| ID: mdl-21075975
ABSTRACT
To support drug development and registration, Caco-2 cell monolayer assays have previously been set up and validated to determine whether candidate drugs are substrates or inhibitors of human P-glycoprotein (P-gp). In this study, the drug-drug interaction (DDI) potential of N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[4-methanesulfonylphenyl]propyl}piperidin-4-yl)-N-ethyl-2-[4-methanesulfonylphenyl]acetamide (AZD5672) was assessed accordingly, and a subsequent clinical digoxin interaction study was performed. AZD5672 (1-500 µM) demonstrated concentration-dependent efflux across cell monolayers, which was abolished in the presence of ketoconazole and quinidine, identifying AZD5672 as a P-gp substrate. In addition, P-gp-mediated digoxin transport was inhibited in a concentration-dependent manner by AZD5672 (IC(50) = 32 µM). Assessment of the calculated theoretical gastrointestinal inhibitor concentration ([I(2)]) and predicted steady-state maximum total plasma inhibitor concentration ([I(1)]) indicated the potential for a DDI at the intestinal but not the systemic level after the predicted therapeutic dose of AZD5672 (100 mg). A clinical study was performed and the plasma pharmacokinetics [observed maximum plasma drug concentration (C(max)) and area under the plasma concentration versus time curve from 0 to 72 h postdose (AUC(0-72 h))] of orally dosed digoxin (0.5 mg) were found to be unaffected by coadministration of AZD5672 (50 mg) at steady state. In contrast, a 150-mg dose of AZD5672 significantly increased digoxin C(max) and AUC(0-72 h) by 1.82- and 1.33-fold, respectively. Concentration-time profile comparisons indicated that digoxin elimination was unchanged by AZD5672, and the interaction was most likely to have resulted from inhibition of intestinal P-gp leading to increased digoxin absorption. The observed dose-dependent clinically significant interaction was accurately predicted using calculated [I(2)] and in vitro P-gp inhibition data, confirming AZD5672 to be a P-gp inhibitor in vivo.
Texto completo:
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Bases de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP
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Benzenoacetamidas
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Interações Medicamentosas
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Modelos Biológicos
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Adolescent
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Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Drug Metab Dispos
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Reino Unido