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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.

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



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).


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.


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.


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.

[Indexed for MEDLINE]

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