PHARMACOKINETICS, ORAL BIOAVAILABILITY, AND METABOLISM IN MICE AND CYNOMOLGUS MONKEYS OF (2'R,5'S-)-CIS-5-FLUORO-1-[2-(HYDROXYMETHYL)-1,3-OXATHIOLAN-5-YL] CYTOSINE, AN AGENT ACTIVE AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS AND HUMAN HEPATITIS-B VIRUS
PHARMACOKINETICS, ORAL BIOAVAILABILITY, AND METABOLISM IN MICE AND CYNOMOLGUS MONKEYS OF (2'R,5'S-)-CIS-5-FLUORO-1-[2-(HYDROXYMETHYL)-1,3-OXATHIOLAN-5-YL] CYTOSINE, AN AGENT ACTIVE AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS AND HUMAN HEPATITIS-B VIRUS
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DOI：
10.1128/aac.38.12.2722
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发表时间：
1994-12-01
影响因子：
4.9
通讯作者：
NELSON, DJ
中科院分区：
文献类型：
--
作者：
FRICK, LW;LAMBE, CU;NELSON, DJ
（2 'R，5 'S-）-cis-5-Fluoro-1-[2-（hydroxymethyl）-1，3-oxathiolan-5-yl] cytosine（524 W 91）是一种核苷类似物，具有体外抗人免疫缺陷病毒和抗人B型肝炎病毒活性。在小鼠中经口和静脉途径给予10、100和600 mg 524 W 91/kg体重后，研究了524 W 91经口给药后的药代动力学和生物利用度。食蟹猴接受10和80 mg 524 W 91/kg给药。在两个种属中，524 W 91通过肾脏快速清除，且与剂量无关。在猴中，10 mg 524 W 91/kg的全身清除率为0.7 +/- 0.1 L/h/kg，稳态分布容积为0.8 +/- 0.02 L/kg。终末消除半衰期为1.0 +/- 0.2 h。10 mg/kg剂量下经口给药后的绝对生物利用度为63% +/- 4%。脑脊液中524 W 91的浓度为血浆中相应水平的4% ± 0.7%。在小鼠中，10 mg 524 W 91/kg的总清除率为2.3 L/kg/h，稳态分布容积为0.9 L/kg。在10 mg/kg剂量下，小鼠经口给药后的绝对生物利用度为96%。在食蟹猴中以80 mg/kg剂量和小鼠中以120 mg/kg剂量研究了经口给予[6-H-3] 524 W 91的代谢。猴在0- 72 h尿液中排泄41% +/- 6%的放射性剂量，在粪便中排泄33% +/- 10%，在笼洗液中排泄10% +/- 7%。原型524 W 91占尿液中回收的总放射性标记药物的64%。主要尿液代谢产物为3 '-亚砜，占尿液中放射性标记物质的27%。葡糖苷酸是一种次要的尿液代谢产物。5-未检出氟尿嘧啶（低于剂量的0.02%）。经口给予120 mg [6-H-3] 524 W 91/kg的小鼠在0- 48 h尿液中排泄67% +/- 7%的放射性标记。在尿液中观察到少量3 '-亚砜和葡糖苷酸代谢产物，但未检出5-氟尿嘧啶。口服给药后良好的生物利用度和代谢抗性建议524 W 91用于进一步临床前评价。
(2'R, 5 'S-)-cis-5-Fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (524W91) is a nucleoside analog with potent anti-human immunodeficiency virus and anti-human hepatitis B virus activities in vitro. The pharmacokinetics and bioavailability of 524W91 after oral dosing were studied in mice dosed with 10, 100, and 600 mg of 524W91 per kg of body weight by the oral and intravenous routes. Cynomolgus monkeys were dosed with 10 and 80 mg of 524W91 per kg. In both species, the clearance of 524W91 was rapid, via the kidney, and was independent of dose. In monkeys, the total body clearance of 10 mg of 524W91 per kg was 0.7 +/- 0.1 liter/h/kg, and the volume of distribution at steady state was 0.8 +/- 0.02 liter/kg. The terminal elimination half-life was 1.0 +/- 0.2 h. The absolute bioavailability after oral dosing was 63% +/- 4% at 10 mg/kg. Concentrations of 524W91 in the cerebrospinal fluid were 4% +/- 0.7% of the corresponding levels in plasma. In mice, the total clearance of 10 mg of 524W91 per kg was 2.3 liters/kg/h, and the volume of distribution at steady state was 0.9 liter/kg. Absolute bioavailability in mice after oral dosing was 96% at a dose of 10 mg/kg. The metabolism of orally administered [6-H-3]524W91 was studied in cynomolgus monkeys at a dose of 80 mg/kg and in mice at a dose of 120 mg/kg. Monkeys excreted 41% +/- 6% of the radioactive dose in the 0- to 72-h urine, 33% +/- 10% in the feces, and 10% +/- 7% in the cage wash. Unchanged 524W91 was 64% of the total radiolabeled drug recovered in the urine. The major urinary metabolite was a 3'-sulfoxide, constituting 27% of the radiolabeled material in the urine. The glucuronide was a minor urinary metabolite. 5-Fluorouracil was not detected (less than 0.02% of the dose). Mice dosed orally with 120 mg of [6-H-3]524W91 per kg excreted 67% +/- 7% of the radiolabel in the 0- to 48-h urine. Small amounts of the 3'-sulfoxide and glucuronide metabolites were observed in the urine, but 5-fluorouracil was not detected. Good bioavailability after oral dosing and resistance to metabolism recommend 524W91 for further preclinical evaluation.