In Vitro and In Situ Evaluation of pH-Dependence of Atazanavir Intestinal Permeability and Interactions with Acid-Reducing Agents
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The objectives of this study were to evaluate the effects of intestinal lumen pH, food intake, and acid-reducing agents on the intestinal permeability of atazanavir, an HIV-1 protease inhibitor.
Atazanavir permeability across Caco-2 cell monolayers (P app) and in situ steady-state permeability across rat jejunum and ileum (P eff) were evaluated in buffers of varied pH (4.5–8.5), in fasted- or fed-state simulated intestinal fluid, or in presence of acid-reducing drugs (e.g., omeprazole).
In vitro accumulation and apical-to-basolateral P app of atazanavir increased with decreasing pH. This effect appeared to be associated with lower atazanavir efflux by P-glycoprotein at acidic pH (5.5) compared to neutral pH. In situ atazanavir P eff across rat jejunum and ileum also decreased 2.7 and 2.3-fold, respectively, when pH was increased from 4.5 to 8.5. Several acid-reducing agents (e.g., omeprazole) moderately inhibited atazanavir efflux in Caco-2 monolayers; however, this effect was not observed in situ. Fed-state buffer significantly increased atazanavir apical-to-basolateral P app (p < 0.001) and in situ P eff (p < 0.05) compared to fasted-state buffer.
Atazanavir permeability is sensitive to changes in intestinal lumen pH. This pH-sensitivity may contribute to atazanavir clinical interactions with acid-reducing agents and variable oral bioavailability.
Key wordsacid-reducing agents atazanavir HIV-1 protease inhibitors intestinal permeability pH dependence
area under the curve
maximum or peak plasma concentration
human immunodeficiency virus
multidrug resistance-associated protein
organic anion transporting polypeptide
simulated intestinal fluid
Acknowledgments and disclosures
This work is supported by an operating grant from the Canadian Foundation for AIDS Research Grant #20023, awarded to Dr. Reina Bendayan. 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 Canadian Institutes of Health Research (CIHR) Frederick Banting and Charles Best – Canada Graduate Scholarship.
We thank Dr. David E. Smith, Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, for excellent guidance with the implementation of the rodent in situ single-pass perfusion technique and Dr. Carolyn Cummins, Department of Pharmaceutical Sciences, University of Toronto, for helpful advice in the design of in vitro and in situ experiments.
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