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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    • "Compounds EC 50 (mM) a CC 50 (mM) a (CEM) HIV-1 (III B ) HIV-2 (ROD) 1 8.4 AE 5.4 8.2 AE 4.0 !50 5 0.030 AE 0.009 0.050 AE 0.005 0.12 AE 0.04 6 0.040 AE 0.003 0.025 AE 0.012 0.14 AE 0.09 7 0.024 AE 0.003 0.019 AE 0.004 0.20 AE 0.04 8 0.056 AE 0.004 0.044 AE 0.003 0.40 AE 0.04 9 0.032 AE 0.002 0.019 AE 0.004 0.045 AE 0.045 10 0.017 AE 0.011 0.007 AE 0.0002 0.019 AE 0.009 2 3.9 AE 0.98 3.7 AE 1.2 >500 11 0.030 AE 0.001 0.014 AE 0.004 6.9 AE 6.4 12 0.004 AE 0.003 0.002 AE 0.0006 1.2 AE 0.1 13 0.019 AE 0.013 0.011 AE 0.001 4.4 AE 0.6 14 0.018 AE 0.009 0.012 AE 0.006 2.3 AE 1.1 15 (ratio 19:1) 0.009 AE 0.002 0.007 AE 0.005 6.9 AE 1.7 16 (ratio 1:5) 0.003 AE 0.0006 0.004 AE 0.002 3.9 AE 1.7 17 0.011 AE 0.0 0.009 AE 0.002 2.0 AE 0.7 GS 7340 0.005 b e 40 b a In CEM cells. b In MT-2 cells [17] "
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    ABSTRACT: The synthesis and in vitro biological evaluation of novel phosphonamidate and phosphonodiamidate prodrugs of adefovir and tenofovir are reported. The selected synthetic approach from free phosphonic acid via bis-trimethylsilyl ester intermediates affords (l)-alanine ester derivatives in 10-70% yields. When assessed for their anti-HIV activity, all the prodrugs showed submicromolar activity. Noteworthy, the most potent derivative in the adefovir series contained a 5,6,7,8-tetrahydronaphtyl group, herein reported for the first time as an aryl moiety in a ProTide. A pronounced cytostatic activity of the above prodrugs is also reported. Selected compounds were tested for their antiproliferative activity against HPV-transformed cells and they were found significantly more active in comparison to their parent compounds. In this study a slightly improved activity of the adefovir derivatives over those of tenofovir was also noticed. However, no specificity for naturally HPV-transformed cell lines was observed.
    European Journal of Medicinal Chemistry 03/2014; 78C:259-268. DOI:10.1016/j.ejmech.2014.03.051 · 3.45 Impact Factor
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    • "In this study, the average drug loading of TFV is 2% (w/w), which means that a 1 mg/ml EuSNa-TFV MS suspension is equivalent to a TFV concentration of 69.7 µM. This is almost 10 times higher than the TFV loading in the pH-sensitive nanoparticles prepared by the emulsion-evaporation technique (Zhang et al., 2011).Given the fact that the EC 50 of TFV is 5.0±2.6 µM, it is reasonably speculated that this MS formulation can provide a sufficient concentration of TFV to exhibit an anti-HIV effect after complete drug release within 2 hours following the vaginal pH change tiggerred by the seminal fluid (Lee et al., 2005). Spray drying as a quick and easy preparation method, not only produces large and spherical particles that have a good impact on powder flowability (Hamdy et al., 2011), but also changes the TFV from its crystallized form. "
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    ABSTRACT: Purpose: To develop spray dried mucoadhesive and pH-sensitive microspheres (MS) based on polymethacrylate salt intended for vaginal delivery of tenofovir (a model HIV microbicide) and assess their critical biological responses. Methods: The formulation variables and process parameters are screened and optimized using a 2(4-1) fractional factorial design. The MS are characterized for size, zeta potential, yield, encapsulation efficiency, Carr's index, drug loading, in vitro release, cytotoxicity, inflammatory responses and mucoadhesion. Results: The optimal MS formulation has an average size of 4.73μm, zeta potential of -26.3mV, 68.9% yield, encapsulation efficiency of 88.7%, Carr's index of 28.3 and drug loading of 2% (w/w). The MS formulation release 91.7% of its payload in the presence of simulated human semen. At a concentration of 1mg/ml, the MS are noncytotoxic to vaginal endocervical/epithelial cells and Lactobacillus crispatus when compared to control media. There is also no statistically significant level of inflammatory cytokine (IL1-α, IL-1β, IL-6, IL-8, and IP-10) release triggered by these MS. Their percent mucoadhesion is 2-fold higher than that of 1% HEC gel formulation. Conclusion: These data suggest the promise of using such MS as an alternative controlled microbicide delivery template by intravaginal route for HIV prevention.
    Antiviral research 12/2012; 97(3). DOI:10.1016/j.antiviral.2012.12.019 · 3.94 Impact Factor
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    ABSTRACT: Discusses practical ways to implement essential principles of TQM (total quality management) within four perspectives: people, quality, mission, and environment. The TQM approach described was developed and implemented at Lockheed Aeronautical Systems Company (LASC) on a very successful medium-scale software-development project: the Ground Processing System Software Update Project (GPSSUP). It is noted that GPSSUP has outperformed previous LASC software development projects according to all major criteria: quality, reliability, profitability, productivity, building personnel capabilities and motivation, schedule performance, and increasing the company technology base. This performance improved as the program progressed, due to a deepening incorporation of TQM via continuous process improvement and a reuse life cycle
    Aerospace and Electronics Conference, 1992. NAECON 1992., Proceedings of the IEEE 1992 National; 06/1992
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