Boom S P, Meyer I, Wouterse A C, Russel F G
Department of Pharmacology, University of Nijmegen, The Netherlands.
Biopharm Drug Dispos. 1998 Apr;19(3):199-208. doi: 10.1002/(sici)1099-081x(199804)19:3<199::aid-bdd1>3.0.co;2-2.
Ranitidine renal clearance was investigated in the beagle dog with or without concomitant infusion of cimetidine or probenecid. Ranitidine was excreted mainly by renal tubular secretion. Plasma clearance was reduced by probenecid from 198 +/- 47 to 119 +/- 41 mL min-1 (mean +/- SD.); renal clearance was reduced from 104 +/- 33 to 54 +/- 24 mL min-1 (p < 0.02) by probenecid and to 89 +/- 37 mL min-1 (NS) by cimetidine. Plasma and urine data were analysed simultaneously with a physiologically based kidney model and were both described adequately by the model, although tubular secretion could not be fully characterized as no saturation was achieved despite high dosages. Tubular secretion of ranitidine was simplified to first-order brush-border and basolateral transport across the proximal tubular cell. Basolateral transport was reduced (from 18.4 +/- 7.8 to 13.6 +/- 10.3 min-1 by cimetidine and 3.9 +/- 3.1 min-1 by probenecid), whereas no effect on brush-border exit was found. Estimated inhibition constants of cimetidine and probenecid were 62 and 4 micrograms mL-1, respectively. Summarizing, ranitidine renal pharmacokinetics were accurately described by the physiologically based kidney model presented in this paper. Model calculations suggest that interaction with cimetidine and probenecid results from competition for basolateral ranitidine uptake into tubular cells.
在伴或不伴西咪替丁或丙磺舒输注的比格犬中研究了雷尼替丁的肾清除率。雷尼替丁主要通过肾小管分泌排泄。丙磺舒使血浆清除率从198±47降至119±41 mL·min⁻¹（均值±标准差）；丙磺舒使肾清除率从104±33降至54±24 mL·min⁻¹（p<0.02），西咪替丁使其降至89±37 mL·min⁻¹（无统计学意义）。血浆和尿液数据用基于生理学的肾脏模型同时进行分析，该模型能充分描述二者情况，尽管由于高剂量下未达到饱和，肾小管分泌不能完全被表征。雷尼替丁的肾小管分泌简化为近端肾小管细胞跨刷状缘和基底外侧的一级转运。基底外侧转运减少（西咪替丁使其从18.4±7.8降至13.6±10.3 min⁻¹，丙磺舒使其降至3.9±3.1 min⁻¹），而对刷状缘排出无影响。西咪替丁和丙磺舒的估计抑制常数分别为62和4 μg·mL⁻¹。总之，本文提出的基于生理学的肾脏模型准确描述了雷尼替丁的肾脏药代动力学。模型计算表明，与西咪替丁和丙磺舒的相互作用是由于竞争雷尼替丁基底外侧摄取进入肾小管细胞所致。
