Au J L, Dalton J T, Wientjes M G
College of Pharmacy, Ohio State University, Columbus.
J Pharmacol Exp Ther. 1991 Jul 1;258(1):357-64.
The hypothesis that weakly acidic drugs are reabsorbed from the urinary bladder was tested using adult female Fischer rats. Bladder reabsorption would have direct implications for pharmacokinetic data analysis of compounds with significant renal excretion. Sodium salicylate (SA) undergoes extensive renal excretion in the rat, and was selected as the model compound. Methodology was developed to administer an intravesical dose to a rat via a transurethral catheter. The barrier function and the integrity of the bladder urothelium were examined by light and electron microscopy, and by monitoring leakage of [14C] inulin (MW 5000) and fluorescein (MW 376). Using these methodologies, we found that urothelial integrity was maintained in about 80% of the animals. Animals that showed tissue damage were excluded from the study. In the pharmacokinetic experiments, one group of animals received an i.v. dose of SA (1.5 or 3 mg/kg), the second group received an intravesical dose of 30 mg/kg (approximately 0.3 ml) and the third group received concomitantly an i.v. tracer dose of [14C] SA and an intravesical dose of unlabeled SA (30 mg/kg). The intravesical dose was removed after 90 min. The intravesical administration of SA produced maximal blood concentrations of 10.8 +/- 5.6 micrograms/ml (mean +/- S.D., n = 10) at 90 to 100 min. The fraction of the intravesical dose recovered after 90 min was between 45 and 75%, which indicates an upper limit of 25 to 55% loss by processes including absorption. The bioavailability of the intravesical dose, calculated from the blood data and the clearance of the i.v. doses, was between 4 and 23% and averaged about 13%.(ABSTRACT TRUNCATED AT 250 WORDS)
使用成年雌性Fischer大鼠对弱酸性药物从膀胱重吸收的假说进行了测试。膀胱重吸收对于具有显著肾排泄的化合物的药代动力学数据分析具有直接影响。水杨酸钠（SA）在大鼠体内经肾脏大量排泄，被选为模型化合物。开发了一种通过经尿道导管向大鼠膀胱内给药的方法。通过光学显微镜和电子显微镜以及监测[14C]菊粉（分子量5000）和荧光素（分子量376）的渗漏来检查膀胱尿路上皮的屏障功能和完整性。使用这些方法，我们发现约80%的动物尿路上皮完整性得以维持。出现组织损伤的动物被排除在研究之外。在药代动力学实验中，一组动物静脉注射SA（1.5或3mg/kg），第二组接受膀胱内给药30mg/kg（约0.3ml），第三组同时接受静脉注射示踪剂量的[14C]SA和膀胱内注射未标记的SA（30mg/kg）。90分钟后去除膀胱内给药剂量。膀胱内给药SA在90至100分钟时产生的最大血药浓度为10.8±5.6μg/ml（平均值±标准差，n = 10）。90分钟后回收的膀胱内给药剂量的比例在45%至75%之间，这表明包括吸收在内的过程导致的损失上限为25%至55%。根据血液数据和静脉注射剂量的清除率计算，膀胱内给药剂量的生物利用度在4%至23%之间，平均约为13%。（摘要截断于250字）
