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Antimicrobial Agents and Chemotherapy, May 2005, p. 1898-1906, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1898-1906.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Selective Intracellular Activation of a Novel Prodrug of the Human Immunodeficiency Virus Reverse Transcriptase Inhibitor Tenofovir Leads to Preferential Distribution and Accumulation in Lymphatic Tissue

William A. Lee,1* Gong-Xin He,1 Eugene Eisenberg,1 Tomas Cihlar,1 Swami Swaminathan,1 Andrew Mulato,1 and Kenneth C. Cundy2

Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404,1 XenoPort, Inc., 3410 Central Expressway, Santa Clara, California 950512

Received 15 July 2004/ Returned for modification 7 October 2004/ Accepted 31 December 2004

An isopropylalaninyl monoamidate phenyl monoester prodrug of tenofovir (GS 7340) was prepared, and its in vitro antiviral activity, metabolism, and pharmacokinetics in dogs were determined. The 50% effective concentration (EC50) of GS 7340 against human immunodeficiency virus type 1 in MT-2 cells was 0.005 µM compared to an EC50 of 5 µM for the parent drug, tenofovir. The (L)-alaninyl analog (GS 7340) was >1,000-fold more active than the (D)-alaninyl analog. GS 7340 has a half-life of 90 min in human plasma at 37°C and a half-life of 28.3 min in an MT-2 cell extract at 37°C. The antiviral activity (>10x the EC50) and the metabolic stability in MT-2 cell extracts (>35x) and plasma (>2.5x) were also sensitive to the stereochemistry at the phosphorus. After a single oral dose of GS 7340 (10 mg-eq/kg tenofovir) to male beagle dogs, the plasma bioavailability of tenofovir compared to an intravenous dose of tenofovir was 17%. The total intracellular concentration of all tenofovir species in isolated peripheral blood mononuclear cells at 24 h was 63 µg-eq/ml compared to 0.2 µg-eq/ml in plasma. A radiolabeled distribution study with dogs resulted in an increased distribution of tenofovir to tissues of lymphatic origin compared to the commercially available prodrug tenofovir DF (Viread).

* Coresponding author. Mailing address: Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404. Phone: (650) 522-5716. Fax: (650) 522-5899. E-mail: Bill_Lee{at}Gilead.com.

Antimicrobial Agents and Chemotherapy, May 2005, p. 1898-1906, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1898-1906.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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