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Antimicrobial Agents and Chemotherapy, October 2006, p. 3297-3304, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00251-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mechanism of Active Renal Tubular Efflux of Tenofovir

Adrian S. Ray,* Tomas Cihlar, Kelly L. Robinson, Leah Tong, Jennifer E. Vela, Michael D. Fuller, Lani M. Wieman, Eugene J. Eisenberg, and Gerry R. Rhodes

Gilead Sciences, Inc., Foster City, California 94404

Received 28 February 2006/ Returned for modification 24 July 2006/ Accepted 27 July 2006

Tenofovir (TFV) undergoes renal elimination by a combination of glomerular filtration and active tubular secretion. While transporter-mediated uptake of TFV from the blood into proximal-tubule cells has been well characterized, comparatively little is known about the efflux system responsible for transporting TFV into the lumen during active tubular secretion. Therefore, members of the ATP-binding cassette family of efflux pumps expressed at the apical side of proximal-tubule cells were studied for the ability to transport TFV. Studies in multiple independent in vitro systems show TFV not to be a substrate for P glycoprotein (Pgp) or multidrug resistance protein type 2 (MRP2). In contrast to Pgp and MRP2, TFV was observed to be a substrate for MRP4. TFV accumulated to fivefold lower levels in MRP4-overexpressing cells, and its accumulation could be increased by an MRP inhibitor. Furthermore, MRP4-overexpressing cells were found to be 2.0- to 2.5-fold less susceptible to cytotoxicity caused by TFV. ATP-dependent uptake of TFV was observed in membrane vesicles containing MRP4 but not in vesicles lacking the transporter. On the basis of these and previous results, the molecular transport pathway for the active tubular secretion of TFV through renal proximal-tubule cells involves uptake from the blood mediated by human organic anion transporters 1 and 3 and efflux into urine by MRP4. A detailed understanding of the molecular mechanism of TFV active tubular secretion will facilitate the assessment of potential renal drug-drug interactions with coadministered agents.

* 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.

Antimicrobial Agents and Chemotherapy, October 2006, p. 3297-3304, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00251-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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