Van der Graaff M, Vermeulen N P, Koperdraat M C, Breimer D D
Arch Int Pharmacodyn Ther. 1986 Aug;282(2):181-95.
In rats, blood concentrations of sparteine (SP) and relative concentrations of sodium borohydride-reducible metabolite following intra-arterial (i.a.) and portal venous administration of SP-sulphate were estimated up to 200 min. In 24 hr urine, unchanged SP was quantitated. Borohydride-reducible metabolite was measured as the difference in SP concentrations before and after reduction. Administration of SP in a dose of 50 mg/kg SP-sulphate i.a. revealed a blood concentration-time profile which did not allow characterization of the terminal half-life or systemic clearance. Therefore, the dose over the area under the curve up to 120 min after administration, CL0-120app, was defined as an apparent average clearance value over the time interval studied. After a dose of 50 mg/kg the CL0-120app was 34.8 +/- 5.9 ml/min/kg when administered i.a. and 80.4 +/- 7.5 ml/min/kg when administered via the portal vein, thus affording an estimate of 0.64 +/- 0.12 for the hepatic extraction ratio. A possible biliary excretion and enterohepatic circulation was studied in rats with a bile fistula. Although SP levels in blood were lower than in control rats, no SP was excreted in the bile and excretion of SP in urine was even slightly higher, which renders circulation of SP itself unlikely. About 25% of the dose was recovered in 180 min bile as borohydride-reducible metabolite, but the urinary excretion of borohydride-reducible metabolite was not changed. The gradual levelling-off of blood concentration versus time curves may partly be explained by the formation of reactive intermediates in the course of metabolism, which inactivate P-450. In support of this, the intrinsic clearance of orally administered hexobarbital (25 mg/kg) was determined 5 and 50 min after i.a. administered SP-sulphate (50 mg/kg), and decreased from 343 +/- 18 to 220 +/- 36 ml/min/kg (p less than 0.05).
在大鼠中，动脉内（i.a.）和门静脉注射硫酸司巴丁（SP）后，测定了长达200分钟的司巴丁（SP）血药浓度以及硼氢化钠可还原代谢物的相对浓度。在24小时尿液中，对未变化的SP进行了定量。硼氢化钠可还原代谢物通过还原前后SP浓度的差值来测定。以50mg/kg硫酸司巴丁的剂量进行动脉内给药，其血药浓度-时间曲线无法确定终末半衰期或全身清除率。因此，给药后120分钟内曲线下面积的剂量清除率CL0-120app被定义为所研究时间间隔内的表观平均清除率值。50mg/kg剂量给药后，动脉内给药时CL0-120app为34.8±5.9ml/min/kg，门静脉给药时为80.4±7.5ml/min/kg，由此得出肝提取率估计值为0.64±0.12。在有胆瘘的大鼠中研究了司巴丁可能的胆汁排泄和肠肝循环。尽管血液中SP水平低于对照大鼠，但胆汁中未排泄出SP，尿液中SP排泄甚至略有增加，这使得SP自身循环不太可能。约25%的剂量在180分钟胆汁中以硼氢化钠可还原代谢物形式回收，但硼氢化钠可还原代谢物的尿排泄未改变。血药浓度-时间曲线的逐渐趋于平稳部分可由代谢过程中反应性中间体的形成来解释，这些中间体使P-450失活。作为对此的支持，在动脉内注射50mg/kg硫酸司巴丁后5分钟和50分钟，测定口服25mg/kg己巴比妥的内在清除率，其从343±18降至220±36ml/min/kg（p＜0.05）。
