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''-DIOXIDE)

被引:17
作者
BALZARINI, J [1 ]
NAESENS, L [1 ]
BOHMAN, C [1 ]
PEREZPEREZ, MJ [1 ]
SANFELIX, A [1 ]
CAMARASA, MJ [1 ]
DECLERCQ, E [1 ]
机构
[1] INST QUIM MED,E-28006 MADRID,SPAIN
关键词
D O I
10.1016/0006-2952(93)90349-2
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
[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 mug/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.
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页码:69 / 77
页数:9
相关论文
共 21 条
[1]   HIGHLY SPECIFIC-INHIBITION OF HUMAN IMMUNODEFICIENCY VIRUS TYPE-1 BY A NOVEL 6-SUBSTITUTED ACYCLOURIDINE DERIVATIVE [J].
BABA, M ;
TANAKA, H ;
DECLERCQ, E ;
PAUWELS, R ;
BALZARINI, J ;
SCHOLS, D ;
NAKASHIMA, H ;
PERNO, CF ;
WALKER, RT ;
MIYASAKA, T .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1989, 165 (03) :1375-1381
[2]   [2',5'-BIS-O-(TERT-BUTYLDIMETHYLSILYL)]-3'-SPIRO-5''-(4''-AMINO-1'',2''-OXATHIOLE-2'',2''-DIOXIDE) (TSAO) DERIVATIVES OF PURINE AND PYRIMIDINE NUCLEOSIDES AS POTENT AND SELECTIVE INHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 [J].
BALZARINI, J ;
PEREZPEREZ, MJ ;
SANFELIX, A ;
VELAZQUEZ, S ;
CAMARASA, MJ ;
DECLERCQ, E .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1992, 36 (05) :1073-1080
[3]   2',5'-BIS-O-(TERT-BUTYLDIMETHYLSILYL)-3'-SPIRO-5''-(4''-AMINO-1',2''-OXATHIOLE-2'',2''-DIOXIDE)PYRIMIDINE (TSAO) NUCLEOSIDE ANALOGS - HIGHLY SELECTIVE INHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 THAT ARE TARGETED AT THE VIRAL REVERSE-TRANSCRIPTASE [J].
BALZARINI, J ;
PEREZPEREZ, MJ ;
SANFELIX, A ;
SCHOLS, D ;
PERNO, CF ;
VANDAMME, AM ;
CAMARASA, MJ ;
DECLERCQ, E .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (10) :4392-4396
[4]  
BALZARINI J, 1992, 3RD P INT S CHEM SYN
[5]   3'-SPIRO NUCLEOSIDES, A NEW CLASS OF SPECIFIC HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INHIBITORS - SYNTHESIS AND ANTIVIRAL ACTIVITY OF [2',5'-BIS-O-(TERT-BUTYLDIMETHYLSILYL)-BETA-D-XYLO AND RIBOFURANOSE]-3'-SPIRO-5''-[4''-AMINO-1'',2''-OXATHIOLE 2'',2''-DIOXIDE] (TSAO) PYRIMIDINE NUCLEOSIDES [J].
CAMARASA, MJ ;
PEREZPEREZ, MJ ;
SANFELIX, A ;
BALZARINI, J ;
DECLERCQ, E .
JOURNAL OF MEDICINAL CHEMISTRY, 1992, 35 (15) :2721-2727
[6]  
DOSHI KJ, 1989, DRUG METAB DISPOS, V17, P590
[7]  
EISEMAN JL, 1988, FASEB J, V2, pA913
[8]   PYRIDINONE DERIVATIVES - SPECIFIC HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE INHIBITORS WITH ANTIVIRAL ACTIVITY [J].
GOLDMAN, ME ;
NUNBERG, JH ;
OBRIEN, JA ;
QUINTERO, JC ;
SCHLEIF, WA ;
FREUND, KF ;
GAUL, SL ;
SAARI, WS ;
WAI, JS ;
HOFFMAN, JM ;
ANDERSON, PS ;
HUPE, DJ ;
EMINI, EA ;
STERN, AM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (15) :6863-6867
[9]   DETERMINATION OF 2',3'-DIDEOXYADENOSINE, 2',3'-DIDEOXYINOSINE AND 2',3'-DIDEOXYCYTIDINE IN BIOLOGICAL SAMPLES [J].
KALIN, JR ;
HILL, DL .
JOURNAL OF CHROMATOGRAPHY-BIOMEDICAL APPLICATIONS, 1988, 431 (01) :184-191
[10]  
KELLEY JA, 1987, DRUG METAB DISPOS, V15, P595