Hsu F H, Prueksaritanont T, Lee M G, Chiou W L
College of Pharmacy, Seoul National University, Korea.
J Pharmacokinet Biopharm. 1987 Aug;15(4):369-86. doi: 10.1007/BF01066519.
The reported incomplete and dose-dependent absorption of chlorothiazide in humans was demonstrated in six rats after five oral solutions at doses of 0.93, 2.55, 9.23, 25.6, and 70.2 mg/kg. Mean 48-hr urinary recoveries of intact drug were 57.3, 50.4, 36.7, 22.8, and 15.3%, respectively. A similar degree of dose dependency in absorption was found in rat, dog, and human when the doses were related to unit body surface area (BSA) but not on unit body weight, indicating similar interspecies absorptive capacity in terms of unit BSA. This finding may be partly rationalized by marked similarities in the reported solution transit time (2-3 hr) in the small intestine as well as in the calculated gross surface area of the small intestine per unit BSA (0.163 for rat and 0.132 for human). Contrary to the previous postulation of a specific absorption site, the drug was absorbed from different regions of the GI tract with apparent 1-hr absorption rates, studied by the in situ closed-loop method, in the following rank order: jejunum (34.6%) greater than duodenum (32.7%) greater than large intestine (20.1%) greater than ileum (18.0%) greater than stomach (12.4%). Different from the commonly assumed first-order absorption process, the intestinal loop absorption was concentration-dependent, suggesting a saturable mechanism. For example, the absorption rate at 0.008 mg/mL was higher than that at 0.2 mg/mL in ileal loops (61%, p less than 0.01) and jejunal loops (22%, p less than 0.1). In addition, the absorption rates at pH 6 and 7.4 were statistically identical, indicating a lack of ionization effect that is important in the passive absorption process. The solubility-limited absorption could probably be ruled out at doses below 2.55 mg/kg for rat and 125 mg for human in view of higher aqueous solubilities at 37 degrees C (e.g., 1.3 mg/mL at pH 7) found in the present study. Contrary to the previous hypothesis of low membrane permeability as a limiting factor for absorption, the "intrinsic" partition coefficient in 1-octanol/aqueous buffer was moderate, 0.6. Furthermore, the absorption in ileal and jejunal loops was enhanced by an apparent increase in mesenteric blood flow by caffeine. The existence of prolonged oral absorption in rats and humans is discussed.
在六只大鼠中，给予剂量分别为0.93、2.55、9.23、25.6和70.2mg/kg的五种口服溶液后，证实了氯噻嗪在人体中报道的吸收不完全且呈剂量依赖性。完整药物的平均48小时尿回收率分别为57.3%、50.4%、36.7%、22.8%和15.3%。当剂量与单位体表面积（BSA）相关而非与单位体重相关时，在大鼠、狗和人体中发现了相似程度的吸收剂量依赖性，这表明就单位BSA而言，种间吸收能力相似。这一发现部分可以通过报道的小肠溶液转运时间（2 - 3小时）以及计算得出的每单位BSA小肠总表面积（大鼠为0.163，人体为0.132）的显著相似性来解释。与先前关于特定吸收部位的假设相反，通过原位闭环法研究发现，药物从胃肠道的不同区域吸收，其1小时的表观吸收速率按以下顺序排列：空肠（34.6%）大于十二指肠（32.7%）大于大肠（20.1%）大于回肠（18.0%）大于胃（12.4%）。与通常假设的一级吸收过程不同，肠袢吸收是浓度依赖性的，提示存在饱和机制。例如，在回肠袢中，0.008mg/mL时的吸收速率高于0.2mg/mL时的吸收速率（61%，p小于0.01），在空肠袢中也是如此（22%，p小于0.1）。此外，pH值为6和7.4时的吸收速率在统计学上相同，表明在被动吸收过程中起重要作用的离子化效应不存在。鉴于本研究中在37℃时较高的水溶性（例如，pH值为7时为1.3mg/mL），对于大鼠剂量低于2.55mg/kg和人体剂量低于125mg时，可能可以排除溶解度限制吸收。与先前关于低膜通透性是吸收限制因素的假设相反，在1 - 辛醇/水性缓冲液中的“内在”分配系数适中，为0.6。此外，咖啡因使肠系膜血流量明显增加，从而增强了回肠和空肠袢中的吸收。文中讨论了大鼠和人体中口服吸收延长的存在情况。
