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

Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 06/2005; 49(5):1898-906. DOI: 10.1128/AAC.49.5.1898-1906.2005
Source: PubMed


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 (>10× the EC50) and the metabolic stability in MT-2 cell extracts (>35×) and plasma (>2.5×) 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).

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