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Role of Drug Efflux and Uptake Transporters in Atazanavir Intestinal Permeability and Drug-Drug Interactions

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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.

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Abbreviations

ABC:

ATP-binding cassette

ARV:

antiretroviral drug

BCRP:

breast cancer resistance protein

CYP:

cytochrome P450

GF120918:

elacridar

HIV:

human immunodeficiency virus

MDR:

multidrug resistance gene

MPP:

1-methyl-4-phenylpyridinium

MRP:

multidrug resistance-associated protein

NNRTI:

non-nucleoside reverse transcriptase inhibitor

NRTI:

nucleoside/nucleotide reverse transcriptase inhibitor

OAT:

organic anion transporter

OATP:

organic anion transporting polypeptide

OCT:

organic cation transporter

Pgp:

p-glycoprotein

PI:

HIV-1 protease inhibitor

PSC833:

valspodar

SLC:

solute carrier

TDF:

tenofovir disoproxil fumarate

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ACKNOWLEDGMENTS AND DISCLOSURES

This work is supported by the Canadian Foundation for AIDS Research [Grant 20023 awarded to RB]. Drs. Reina Bendayan and Sharon Walmsley are recipients of the Ontario HIV Treatment Network (OHTN) Career Scientist award. Ms. Olena Kis was supported by Ph.D. studentships from the OHTN, Ministry of Health of Ontario, and the National Science and Engineering Research Council of Canada (NSERC) and is currently a recipient of the Canadian Institutes of Health Research (CIHR) Frederick Banting and Charles Best—Canada Graduate Scholarship. Dr. Jason Zastre was a postdoctoral fellow in the laboratory or Dr. Reina Bendayan when this study was initiated and is currently an Assistant Professor in the Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy University of Georgia, Athens, Georgia.

We thank Dr. David E. Smith (Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy) for providing excellent guidance with the implementation of the rodent in situ single-pass perfusion technique.

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Author notes

  1. Jason A. Zastre

    Present address: Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, University of Georgia, Athens, Georgia, USA

Authors and Affiliations

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

    Olena Kis, Jason A. Zastre, Md. Tozammel Hoque & Reina Bendayan

  2. Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    Sharon L. Walmsley

  3. Division of Infectious Diseases, University Health Network, Toronto, Ontario, Canada

    Sharon L. Walmsley

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  1. Olena Kis
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  2. Jason A. Zastre
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  4. Sharon L. Walmsley
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  5. Reina Bendayan
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Correspondence to Reina Bendayan.

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Kis, O., Zastre, J.A., Hoque, M.T. et al. Role of Drug Efflux and Uptake Transporters in Atazanavir Intestinal Permeability and Drug-Drug Interactions. Pharm Res 30, 1050–1064 (2013). https://doi.org/10.1007/s11095-012-0942-y

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