Metabolism and pharmacokinetics of the anti-HIV-1-specific inhibitor [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3-N- methyl-thymine]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dio xide).
[1-[2',5'-Bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3-N- methyl-thymine]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''- dioxide) (TSAO-m3T) is a potent, selective and specific inhibitor of human immunodeficiency virus type 1 replication in vitro. Uptake of TSAO-m3T by human CEM cells is drug concentration-dependent and increased proportionally with increasing initial extracellular TSAO-m3T concentrations up to 20 micrograms/mL. Within 6 hr of incubation, the cells were almost completely saturated with the test compound; further incubation up to 72 hr did not markedly increase the intracellular concentration of the compound. No intracellular metabolic conversion of TSAO-m3T was observed in CEM, MT-4 or MOLT-4 cells. Upon intravenous bolus administration of TSAO-m3T to mice at 0.75 mg/kg, TSAO-m3T was rapidly cleared from the plasma in a mono-exponential manner (half-life: 22 min; distribution volume: 9.5 L/kg; total body clearance: 17.8 L/hr/kg). TSAO-m3T mainly accumulated in the lungs, followed by the heart, kidney and liver. Significant amounts of different metabolites of TSAO-m3T were detected in most tissues, the liver, kidney and spleen being the organs that showed the most extensive metabolism. The principal metabolites identified were TSAO-m3T derivatives in which the t-butyldimethylsilyl moiety at C-2' and/or C-5' had been split off. The free base N3-methylthymine was not detected.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Naesens
L
L
Bohman
C
C
Pérez-Pérez
M J
MJ
San-Félix
A
A
Camarasa
M J
MJ
De Clercq
E
E
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006207:Half-Life; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D008956:Models, Chemical; D013141:Spiro Compounds / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D013937:Thymidine Kinase / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000378:metabolism; D014018:Tissue Distribution; D014316:Tritium; D014529:Uridine / Q000031:analogs & derivatives
D000998:Antiviral Agents; D013141:Spiro Compounds; D014316:Tritium; C082493:1-(2',5'-bis-O-(tert-butyldimethylsilylribofuranosyl)-3-N-methylthymine)-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide); C012439:methylthymidine; D013939:Thymidine Phosphorylase; D013937:Thymidine Kinase; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine