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

• DOI: 10.1128/aac.49.5.1898-1906.2005
• Publication Date: 2005-04-26T23:32:47Z
• Authors: William A. Lee; Gong-Xin He; Eugene Eisenberg; Tomas Cihlar; Swami Swaminathan; Andrew Mulato; Kenneth C. Cundy
• Keywords: Reverse-transcriptase inhibitor; Half-life

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