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Antimicrobial Agents and Chemotherapy, October 2007, p. 3498-3504, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00671-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Effects of Human Immunodeficiency Virus Protease Inhibitors on the Intestinal Absorption of Tenofovir Disoproxil Fumarate In Vitro{triangledown}

Leah Tong,1 Truc K. Phan,1 Kelly L. Robinson,1 Darius Babusis,1 Robert Strab,2 Siddhartha Bhoopathy,2 Ismael J. Hidalgo,2 Gerald R. Rhodes,1 and Adrian S. Ray1*

Gilead Sciences, Inc., Foster City, California 94404,1 Absorption Systems, L. P., Exton, Pennsylvania 193412

Received 22 May 2007/ Returned for modification 5 July 2007/ Accepted 19 July 2007

Human immunodeficiency virus protease inhibitors (PIs) modestly affect the plasma pharmacokinetics of tenofovir (TFV; –15% to +37% change in exposure) following coadministration with the oral prodrug TFV disoproxil fumarate (TDF) by a previously undefined mechanism. TDF permeation was found to be reduced by the combined action of ester cleavage and efflux transport in vitro. Saturable TDF efflux observed in Caco-2 cells suggests that at pharmacologically relevant intestinal concentrations, transport has only a limited effect on TDF absorption, thus minimizing the magnitude of potential intestinal drug interactions. Most tested PIs increased apical-to-basolateral TDF permeation and decreased secretory transport in MDCKII cells overexpressing P-glycoprotein (Pgp; MDCKII-MDR1 cells) and Caco-2 cells. PIs were found to cause a multifactorial effect on the barriers to TDF absorption. All PIs showed similar levels of inhibition of esterase-dependent degradation of TDF in an intestinal subcellular fraction, except for amprenavir, which was found to be a weaker inhibitor. All PIs caused a dose-dependent increase in the accumulation of a model Pgp substrate in MDCKII-MDR1 cells. Pgp inhibition constants ranged from 10.3 µM (lopinavir) to >100 µM (amprenavir, indinavir, and darunavir). Analogous to hepatic cytochrome P450-mediated drug interactions, we propose that the relative differences in perturbations in TFV plasma levels when TDF is coadministered with PIs are based in part on the net effect of inhibition and induction of intestinal Pgp by PIs. Combined with prior studies, these findings indicate that intestinal absorption is the mechanism for changes in TFV plasma levels when TDF is coadministered with PIs.

* Corresponding author. Mailing address: Department of Drug Metabolism, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404. Phone: (650) 522-5536. Fax: (650) 522-1892. E-mail: adrian.ray{at}gilead.com

{triangledown} Published ahead of print on 30 July 2007.

Antimicrobial Agents and Chemotherapy, October 2007, p. 3498-3504, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00671-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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  • Gagnieu, M.-C., Barkil, M. E., Livrozet, J.-M., Cotte, L., Miailhes, P., Boibieux, A., Guitton, J., Tod, M. (2008). Population Pharmacokinetics of Tenofovir in AIDS Patients. J Clin Pharmacol 48: 1282-1288 [Abstract] [Full Text]  


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