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Antimicrobial Agents and Chemotherapy, January 2009, p. 150-156, Vol. 53, No. 1
0066-4804/09/$08.00+0     doi:10.1128/AAC.01183-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Novel Nucleotide Human Immunodeficiency Virus Reverse Transcriptase Inhibitor GS-9148 with a Low Nephrotoxic Potential: Characterization of Renal Transport and Accumulation{triangledown}

Tomas Cihlar,1* Genevieve LaFlamme,1 Robyn Fisher,2 Anne C. Carey,1 Jennifer E. Vela,1 Richard Mackman,1 and Adrian S. Ray1

Gilead Sciences, Inc., Foster City, California,1 Vitron, Inc., Tucson, Arizona2

Received 5 September 2008/ Returned for modification 17 October 2008/ Accepted 28 October 2008

Accumulation of antiviral nucleotides in renal proximal tubules is controlled by their basolateral uptake via the human renal organic anion transporters type 1 (hOAT1) and 3 (hOAT3) and apical efflux via the multidrug resistance protein 4 (MRP4). GS-9148 is a novel ribose-modified nucleotide human immunodeficiency virus (HIV) reverse transcriptase inhibitor, and its oral prodrug GS-9131 is currently being evaluated in the clinic as an anti-HIV agent. To assess the potential of GS-9148 for nephrotoxicity, its mechanism of renal transport, cytotoxicity, and renal accumulation were explored in vitro and in vivo. In comparison with the acyclic nucleotides cidofovir, adefovir, and tenofovir, GS-9148 showed 60- to 100-fold lower efficiency of transport (Vmax/Km) by hOAT1 and was 20- to 300-fold less cytotoxic in cells overexpressing hOAT1, indicating its lower hOAT1-mediated intracellular accumulation and reduced intrinsic cytotoxicity. GS-9148 was also relatively inefficiently transported by hOAT3. Similar to acyclic nucleotides, GS-9148 was a substrate for MRP4 as evidenced by its reduced intracellular retention in cells overexpressing the efflux pump. Consistent with these molecular observations, GS-9148 was inefficiently taken up by fresh human renal cortex tissue in vitro and showed a limited accumulation in kidneys in vivo following oral administration of [14C]GS-9131 to dogs. Compared to acyclic nucleotide analogs, GS-9148 was also found to have lower net active tubular secretion in dogs. Collectively, these results suggest that GS-9148 exhibits a low potential for renal accumulation and nephrotoxicity.

* Corresponding author. Mailing address: Department of Biology, Gilead Sciences, 362 Lakeside Dr., Foster City, CA 94404. Phone: (650) 522-5637. Fax: (650) 522-5890. E-mail: tomas.cihlar{at}gilead.com

{triangledown} Published ahead of print on 10 November 2008.

Antimicrobial Agents and Chemotherapy, January 2009, p. 150-156, Vol. 53, No. 1
0066-4804/09/$08.00+0     doi:10.1128/AAC.01183-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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