title: 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.
abstract: 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 (EC(50)) of GS 7340 against human immunodeficiency virus type 1 in MT-2 cells was 0.005 microM compared to an EC(50) of 5 microM 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 degrees C and a half-life of 28.3 min in an MT-2 cell extract at 37 degrees C. The antiviral activity (>10 x the EC(50)) and the metabolic stability in MT-2 cell extracts (>35 x) and plasma (>2.5 x) 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 microg-eq/ml compared to 0.2 microg-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).
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA. Bill_Lee@Gilead.com
authors.forename: William A
authors.initials: WA
authors.lastname: Lee
authors.forename: Gong-Xin
authors.initials: GX
authors.lastname: He
authors.forename: Eugene
authors.initials: E
authors.lastname: Eisenberg
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
authors.forename: Swami
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Andrew
authors.initials: A
authors.lastname: Mulato
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Cundy
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000409:Alanine; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D019540:Area Under Curve; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D015497:HIV-1; D006801:Humans; D066298:In Vitro Techniques; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D063065:Organophosphonates / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet; D000068698:Tenofovir / Q000031:analogs & derivatives; D014018:Tissue Distribution
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine