Zimmerman C L, Remmel R P, Ibrahim S S, Beers S A, Vince R
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Drug Metab Dispos. 1992 Jan-Feb;20(1):47-51.
The recently synthesized carbocyclic 2',3'-didehydro-2',3'-dideoxy-6-deoxy-6-amino-guanosine [(-)6AC] was evaluated as a prodrug for carbovir, carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine [(-)CBV] in seven male Sprague-Dawley rats. A randomized three-way cross-over design was used. Rats were assigned to receive the following treatments: a 20 mg/kg (-)6AC infusion, 40 mg/kg (-)6AC orally, and a 20 mg/kg (-)CBV infusion. Blood samples were collected over 480 min, and urine was collected for up to 48 hr. A 2- to 3-day washout period was observed between treatments. Following i.v. infusion, (-)6AC concentrations in the blood declined rapidly in a monoexponential pattern with an elimination half-life of 11.3 +/- 3.3 min (mean +/- SD, n = 7). The time-averaged total body clearance was 115.7 +/- 32.6 ml/min/kg. The fraction of the dose excreted unchanged in urine was 0.28 +/- 0.06. The fraction of the (-)6AC dose metabolized to (-)CBV was 0.48 +/- 0.14. Following oral administration of (-)6AC, the bioavailability of (-)CBV was 46.2 +/- 9.9% (n = 6) in comparison with the bioavailability of approximately 20% previously obtained after an oral dose of (-)CBV. The Cmax of (-)CBV after a 40 mg/kg oral dose of (-)6AC was 1.65 +/- 0.7 micrograms/ml as compared with the previously reported Cmax of 1.00 microgram/ml obtained after a 60 mg/kg oral dose of (-)CBV. (-)6AC has considerable potential for the improvement of the extent of absorption of (-)CBV from oral dosing.
最近合成的碳环2',3'-二脱氢-2',3'-二脱氧-6-脱氧-6-氨基鸟苷[(-)6AC]在7只雄性Sprague-Dawley大鼠中被评估为碳环胞苷（碳环2',3'-二脱氢-2',3'-二脱氧鸟苷[(-)CBV]）的前体药物。采用随机三交叉设计。大鼠被分配接受以下治疗：20mg/kg (-)6AC静脉输注、40mg/kg (-)6AC口服以及20mg/kg (-)CBV静脉输注。在480分钟内采集血样，并收集尿液长达48小时。各治疗之间观察到2至3天的洗脱期。静脉输注后，血液中(-)6AC浓度以单指数模式迅速下降，消除半衰期为11.3±3.3分钟（平均值±标准差，n = 7）。时间平均全身清除率为115.7±32.6ml/min/kg。尿液中以原形排泄的剂量分数为0.28±0.06。(-)6AC剂量代谢为(-)CBV的分数为0.48±0.14。口服(-)6AC后，(-)CBV的生物利用度为46.2±9.9%（n = 6），而之前口服(-)CBV剂量后获得的生物利用度约为20%。40mg/kg口服(-)6AC后(-)CBV的Cmax为1.65±0.7μg/ml，而之前报道60mg/kg口服(-)CBV后获得的Cmax为1.00μg/ml。(-)6AC在改善口服给药时(-)CBV的吸收程度方面具有相当大的潜力。
