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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Pharmacokinetics of oral and intravenous dolasetron mesylate in patients with renal impairment.
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Pharmacokinetics of oral and intravenous dolasetron mesylate in patients with renal impairment.

机译：肾功能不全患者口服和静脉注射甲磺酸dolasetron的药代动力学。

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In an open-label, randomized, two-way complete crossover study, the influence of renal impairment on the pharmacokinetics of dolasetron and its primary active metabolite, hydrodolasetron, were evaluated. Patients with renal impairment were stratified into three groups of 12 based on their 24-hour creatinine clearance (Cl(cr)): group 1, mild impairment (Cl(cr) between 41 and 80 mL/min); group 2, moderate impairment (Cl(cr) between 11 and 40 mL/min); and group 3, endstage renal impairment (Cl(cr) < or = 10 mL/min). Twenty-four healthy volunteers from a previous study served as the control group. Each participant received a single intravenous or oral 200-mg dose of dolasetron mesylate on separate occasions. Serial blood samples were collected up to 60 hours after dose for determination of dolasetron and hydrodolasetron, and urine samples were collected in intervals up to 72 hours for determination of dolasetron, hydrodolasetron, and the 5' and 6'-hydroxy metabolites of hydrodolasetron. Because plasma concentrations were low and sporadic, pharmacokinetic parameters of dolasetron were not calculated after oral administration. Although some significant differences in area under the concentration-time curve (AUC0-infinity), volume of distribution (Vd), systemic clearance (Cl), and elimination half-life (t1/2) of the parent drug were observed between control subjects and patients with renal impairment, there were no systematic findings related to degree of renal dysfunction. The elimination pathways of hydrodolasetron include both hepatic metabolism and renal excretion. Consistent increases in mean Cmax, AUC0-infinity, and t1/2 and decreases in renal and total apparent clearance of hydrodolasetron were seen with diminishing renal function after intravenous administration of dolasetron mesylate. No consistent changes were found after oral administration. Urinary excretion of hydrodolasetron and its metabolites decreased with decreasing renal function, but the profile of metabolites remained constant. Dolasetron was well tolerated in all three groups of patients. Based on these findings, no dosage adjustment for dolasetron is recommended in patients with renal impairment.
机译：在一项开放标签，随机，双向双向交叉研究中，评估了肾功能不全对dolasetron及其主要活性代谢物hydrodolasetron药代动力学的影响。肾功能不全的患者根据其24小时肌酐清除率（Cl（cr））分为三组，每组12组：第1组，轻度损伤（Cl（cr）在41至80 mL / min之间）;第1组为轻度损伤（Cl（cr）在41至80 mL / min之间）。第2组，中度损伤（Cl（cr）在11至40 mL / min之间）;第3组，终末期肾功能不全（Cl（cr）<或= 10 mL / min）。来自先前研究的24名健康志愿者作为对照组。每位参与者分别在不同的场合接受单次静脉或口服200毫克剂量的甲磺酸多拉西酮。给药后60小时内收集系列血样，用于测定多拉西酮和氢多拉西酮，间隔至多72小时收集尿液样品，用于测定多拉西酮，氢多拉西酮以及氢多拉西酮的5'和6'-羟基代谢产物。由于血浆浓度低且偶发，口服后不计算多拉西酮的药代动力学参数。尽管在对照组之间观察到母体药物的浓度-时间曲线下面积（AUC0-无穷大），分布体积（Vd），全身清除率（Cl）和消除半衰期（t1 / 2）有一些显着差异对于肾功能不全的患者，没有与肾功能不全程度相关的系统性发现。加氢多拉西酮的消除途径包括肝代谢和肾脏排泄。静脉注射甲磺酸多拉西酮后，观察到氢多拉西酮的平均Cmax，AUC0-无穷大和t1 / 2一致增加，肾脏和总表观清除率降低，肾功能下降。口服后未发现一致变化。氢肾上腺皮质激素及其代谢物的尿排泄随着肾功能的降低而减少，但代谢物的分布保持恒定。在所有三组患者中，Dolasetron的耐受性均良好。基于这些发现，对于肾功能不全的患者，不建议调整多拉司琼的剂量。

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