Frick L W, St John L, Taylor L C, Painter G R, Furman P A, Liotta D C, Furfine E S, Nelson D J
Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709, USA.
Antimicrob Agents Chemother. 1993 Nov;37(11):2285-92. doi: 10.1128/AAC.37.11.2285.
The pharmacokinetics and metabolism of the potent anti-human immunodeficiency virus and anti-hepatitis B virus compound, (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (FTC), were investigated in male CD rats. Plasma clearance of 10 mg of FTC per kg of body weight was biexponential in rats, with a half-life at alpha phase of 4.7 +/- 1.1 min (mean +/- standard deviation) and a half-life at beta phase of 44 +/- 8.8 min (n = 5). The total body clearance of FTC was 1.8 +/- 0.1 liters/h/kg, and the oral bioavailability was 90% +/- 8%. The volume of distribution at steady state (Vss) was 1.5 +/- 0.1 liters/kg. Increasing the dose to 100 mg/kg slowed clearance to 1.5 +/- 0.2 liters/kg/h, lowered the Vss to 1.2 +/- 0.2 liters/kg, and reduced the oral bioavailability to 65% +/- 15%. FTC in the brains of rats was initially less than 2% of the plasma concentration but increased to 6% by 2 h postdose. Probenecid elevated levels of FTC in plasma as well as in brains but did not alter the brain-to-plasma ratio. The urinary and fecal recoveries of unchanged FTC after a 10-mg/kg intravenous dose were 87% +/- 3% and 5% +/- 1.6%, respectively. After a 10-mg/kg oral dose, respective urinary and fecal recoveries were 70% +/- 2.5% and 25% +/- 1.6%. Two sulfoxides of FTC were observed in the urine, accounting for 0.4% +/- 0.03% and 2.7% +/- 0.2% of the intravenous dose and 0.4% +/- 0.06% and 2.5% +/- 0.3% of the oral dose. Also observed were 5-fluorocytosine, representing 0.4% +/- 0.06% of the intravenous dose and 0.4% +/- 0.07% of the oral dose, and FTC glucuronide, representing 0.7% +/- 0.2% of the oral dose and 0.4% +/- 0.2% of the intravenous dose. Neither deaminated FTC nor 5-fluorouracil was observed in the urine (less than 0.2% of dose). The high oral availability and minimal metabolism of FTC encourage its further preclinical development.
在雄性CD大鼠中研究了强效抗人类免疫缺陷病毒和抗乙型肝炎病毒化合物（-）-顺式-5-氟-1-[2-（羟甲基）-1,3-氧硫杂环戊烷-5-基]胞嘧啶（FTC）的药代动力学和代谢情况。每千克体重给予10mg FTC时，大鼠的血浆清除呈双指数型，α相半衰期为4.7±1.1分钟（平均值±标准差），β相半衰期为44±8.8分钟（n = 5）。FTC的全身清除率为1.8±0.1升/小时/千克，口服生物利用度为90%±8%。稳态分布容积（Vss）为1.5±0.1升/千克。将剂量增加到100mg/kg会使清除率减慢至1.5±0.2升/千克/小时，Vss降至1.2±0.2升/千克，并使口服生物利用度降至65%±15%。大鼠脑中的FTC最初低于血浆浓度的2%，但给药后2小时增加到6%。丙磺舒提高了血浆和脑中FTC的水平，但未改变脑-血浆比率。静脉注射10mg/kg剂量后，未变化的FTC经尿液和粪便的回收率分别为87%±3%和5%±1.6%。口服10mg/kg剂量后，尿液和粪便的回收率分别为70%±2.5%和25%±1.6%。在尿液中观察到FTC的两种亚砜，分别占静脉注射剂量的0.4%±0.03%和2.7%±0.2%，以及口服剂量的0.4%±0.06%和2.5%±0.3%。还观察到5-氟胞嘧啶，分别占静脉注射剂量的0.4%±0.06%和口服剂量的0.4%±0.07%，以及FTC葡糖醛酸，分别占口服剂量的0.7%±0.2%和静脉注射剂量的0.4%±0.2%。尿液中未观察到脱氨基FTC和5-氟尿嘧啶（低于剂量的0.2%）。FTC的高口服生物利用度和最小代谢情况促使其进一步进行临床前开发。
