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Pharm Res. 2013 Apr;30(4):1050-64. doi: 10.1007/s11095-012-0942-y. Epub 2012 Dec 7.

Role of drug efflux and uptake transporters in atazanavir intestinal permeability and drug-drug interactions.

Author information

1
Department of Pharmaceutical Sciences Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Room 1001, Toronto, Ontario, M5S 3M2, Canada.

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.

PMID:
23224979
DOI:
10.1007/s11095-012-0942-y
[Indexed for MEDLINE]

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