Role of drug efflux and uptake transporters in atazanavir intestinal permeability and drug-drug interactions.
Pharm Res
; 30(4): 1050-64, 2013 Apr.
Article
em En
| MEDLINE
| ID: mdl-23224979
ABSTRACT
PURPOSE:
To investigate the role of membrane-associated drug transporters in regulating the intestinal absorption of the HIV-1 protease inhibitor, atazanavir, and assess the potential contribution of these transporters in clinical interactions of atazanavir with other protease inhibitors and tenofovir disoproxil fumarate (TDF).METHODS:
Intestinal permeability of atazanavir was investigated in vitro, using the Caco-2 cell line system grown on Transwell inserts, and in situ, by single-pass perfusion of rat intestinal segments, jejunum and ileum, in the absence or presence of standard transporter inhibitors or antiretroviral drugs.RESULTS:
Atazanavir accumulation by Caco-2 cells was susceptible to inhibition by P-glycoprotein and organic anion transporting polypeptide (OATP) family inhibitors and several antiretroviral drugs (protease inhibitors, TDF). The secretory flux of atazanavir (basolateral-to-apical Papp) was 11.7-fold higher than its absorptive flux. This efflux ratio was reduced to 1.5-1.7 in the presence of P-glycoprotein inhibitors or ritonavir. P-glycoprotein inhibition also resulted in 1.5-2.5-fold increase in atazanavir absorption in situ. Co-administration of TDF, however, reduced atazanavir intestinal permeability by 13-49%, similar to the effect observed clinically.CONCLUSIONS:
Drug transporters such as P-glycoprotein and OATPs regulate intestinal permeability of atazanavir and may contribute to its poor oral bioavailability and drug-drug interactions with other protease inhibitors and TDF.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oligopeptídeos
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Piridinas
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP
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Fármacos Anti-HIV
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Transportadores de Ânions Orgânicos
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Absorção Intestinal
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article