Thürmann P A, Harder S, Wolter K, Münck A C, Fritschka E
Department of Clinical Pharmacology, University Hospital Frankfurt/Main, Germany.
Clin Nephrol. 1997 Feb;47(2):99-105.
The pharmacokinetics of the PDGF-antagonist trapidil and its major metabolite desethyl-trapidil (M 1) were studied in patients with and without renal failure after a single dose of 200 mg and following 4-day treatment with 200 mg t.i.d. Twenty patients were classified according to their renal function as assessed by creatinine clearance (C(Cr)) in group A: 133.7 +/- 30.3 ml/min (n = 8), group B: 63.6 +/- 15.4 ml/min (n = 6) and group C: 17.9 +/- 6.1 ml/min (n = 6), patients on hemodialysis were not enrolled. After the first dose maximal plasma concentrations of trapidil with 5.99 +/- 1.60 (A), 5.76 +/- 1.46 (B) and 5.63 +/- 1.53 micrograms/ml (C) were not different between groups, but somewhat lower on day 4 with 4.96 +/- 0.78 (A), 5.78 +/- 1.78 (B) and 5.47 +/- 1.42 micrograms/ml (C). Similarly, AUC0-infinity-values on day 1 with 16.9 +/- 4.8 (A), 20.2 +/- 6.7 (B) and 22.2 +/- 11.2 micrograms/ml x h (C) showed only modest (NS) differences between groups, but decreased markedly on day 4 to 10.8 +/- 1.8 (A), 13.6 +/- 5.8 (B) and 14.4 +/- 4.3 micrograms/ml x h (C). Linear regression analysis between AUC and C(Cr) demonstrated no relationship between these parameters. For plasma concentrations of M 1 no significant differences were seen between groups. At steady state maximal plasma concentrations of M 1 occurred earlier and were slightly increased. In one patient (group B) receiving tamoxifen comedication markedly elevated plasma concentrations of trapidil and desethyltrapidil occurred, suggesting a pharmacokinetic interaction. Trapidil may be safely given to patients with impaired renal function, the apparent decrease of trapidil plasma concentrations may suggest autoinduction of metabolizing enzymes.
在单次给予200毫克剂量以及每日3次、每次200毫克、连续治疗4天后，对有和没有肾衰竭的患者研究了血小板衍生生长因子拮抗剂曲匹地尔及其主要代谢物去乙基曲匹地尔（M1）的药代动力学。根据肌酐清除率（C(Cr)）评估的肾功能，将20名患者分为A组：133.7±30.3毫升/分钟（n = 8）、B组：63.6±15.4毫升/分钟（n = 6）和C组：17.9±6.1毫升/分钟（n = 6），未纳入接受血液透析的患者。首次给药后，曲匹地尔的最大血浆浓度在A组为5.99±1.60、B组为5.76±1.46、C组为5.63±1.53微克/毫升，各组之间无差异，但在第4天有所降低，A组为4.96±0.78、B组为5.78±1.78、C组为5.47±1.42微克/毫升。同样，第1天的AUC0-∞值在A组为16.9±4.8、B组为20.2±6.7、C组为22.2±11.2微克/毫升·小时，各组之间仅存在适度（无统计学意义）差异，但在第4天显著下降至A组为10.8±1.8、B组为13.6±5.8、C组为14.4±4.3微克/毫升·小时。AUC与C(Cr)之间的线性回归分析表明这些参数之间无相关性。对于M1的血浆浓度，各组之间未见显著差异。在稳态时，M1的最大血浆浓度出现得更早且略有升高。在一名同时服用他莫昔芬的患者（B组）中，曲匹地尔的血浆浓度显著升高，且出现了去乙基曲匹地尔，提示存在药代动力学相互作用。肾功能受损的患者可以安全地使用曲匹地尔，曲匹地尔血浆浓度的明显下降可能提示代谢酶的自身诱导。
