Garrett E R, Roseboom H, Green J R, Schuermann W
Int J Clin Pharmacol Biopharm. 1978 May;16(5):193-208.
The pharmacokinetics of completely metabolized papaverine hydrochloride were characterized by a linear sum of three exponentials on intravenous administration with respective 1.5, 19 and 107 min apparent half lives. There was a time-dependent partition from plasma water into red blood cells with an apparent half life of 1.5--3 min. The partition coefficient normally ranged between 8 and 15 at therapeutic levels but approached unity at high plasma concentrations to indicate a saturable partition. Apparent compartmental volumes of distribution referenced to total concentrations in the plasma were 4.3--4.8, 11--13 and 20--25 liters. Protein binding was 91--95%. The hepatic clearance of blood was 960 ml/min, corresponding to a hepatic efficiency of 69%, and indicated that the clearance of protein-bound drug was consistent with the observed first pass metabolism of 70% for oral solutions. No dose dependency was observed on intravenous administration or on oral administration of solutions and tablets. Tablets with release lag times of 10--15 min showed relative bioavailabilities of 52%. Two different lots of sustained release capsules showed 68 and 89% relative bioavailabilities. Release lag times among capsules ranged between 0 and 170 min. Loo-Riegelman calculations and analog computer fittings were consistent with a half life of absorption from oral solutions of 19 min and zero order release rates from tablets and sustained release capsules. Chronic studies of tablets q.i.d. and capsules b.i.d. confirmed lack of accumulation. An appropriately designed 300 mg sustained release capsule, b.i.d., for an arbitrary plasma level of 0.200 microgram/ml should have one tenth the release rate of the studied capsules.
静脉注射完全代谢的盐酸罂粟碱后，其药代动力学特征表现为三个指数项的线性和，各自的表观半衰期分别为1.5、19和107分钟。存在从血浆水向红细胞的时间依赖性分配，表观半衰期为1.5 - 3分钟。在治疗水平下，分配系数通常在8至15之间，但在高血浆浓度时接近1，表明存在饱和分配。以血浆总浓度为参考的表观分布室容积为4.3 - 4.8升、11 - 13升和20 - 25升。蛋白结合率为91 - 95%。肝脏的血液清除率为960毫升/分钟，对应肝脏清除效率为69%，这表明蛋白结合药物的清除与口服溶液观察到的70%的首过代谢一致。静脉给药或口服溶液及片剂时均未观察到剂量依赖性。释放滞后时间为10 - 15分钟的片剂相对生物利用度为52%。两批不同的缓释胶囊相对生物利用度分别为68%和89%。胶囊之间的释放滞后时间在0至170分钟之间。Loo - Riegelman计算和模拟计算机拟合结果与口服溶液19分钟的吸收半衰期以及片剂和缓释胶囊的零级释放速率一致。每日四次服用片剂和每日两次服用胶囊的长期研究证实无蓄积现象。对于任意血浆水平为0.200微克/毫升的情况，一个设计合理的300毫克缓释胶囊，每日两次服用，其释放速率应为所研究胶囊的十分之一。
