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.
Antimicrob Agents Chemother
; 49(5): 1898-906, 2005 May.
Article
em En
| MEDLINE
| ID: mdl-15855512
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).
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pró-Fármacos
/
Adenina
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Inibidores da Transcriptase Reversa
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Organofosfonatos
/
Sistema Linfático
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Antimicrob Agents Chemother
Ano de publicação:
2005
Tipo de documento:
Article
País de afiliação:
Estados Unidos