Effect of liver impairment on the pharmacokinetics of tolcapone and its metabolites
Effect of liver impairment on the pharmacokinetics of tolcapone and its metabolites
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DOI：
10.1016/s0009-9236(98)90088-1
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发表时间：
1998-06-01
影响因子：
6.7
通讯作者：
van Hattum, J
中科院分区：
文献类型：
--
作者：
Jorga, KM;Kroodsma, JM;van Hattum, J
目的：评估肝损害对托尔卡酮药代动力学的影响，并为正在接受帕金森病治疗的患者提供合适的剂量建议。研究设计：在一项开放的双向交叉研究中，16名中度肝病患者（8名肝硬化患者和8名非肝硬化肝病患者）和8名健康受试者在不同的场合口服剂量200mg托卡彭和静脉剂量50mg托卡彭。测定血浆和尿液中总tolcapone和未结合tolcapone及其三种主要代谢物（tolcapone glucuronide、羧酸和3-O-methyl代谢物）的浓度。结果：在药物总浓度基础上，各组间托尔卡彭药代动力学β差异较小。然而，肝硬化患者中未结合药物的清除率和分布量均低于对照组。无药理活性的葡萄糖醛酸代谢物在肝硬化患者的血浆浓度升高。结论：肝硬化患者应给予推荐剂量的一半托卡彭，以维持非结合药物的目标稳态浓度，并避免托卡彭葡糖苷的积累，我们的数据表明，在存在中度慢性肝炎的情况下，不需要调整剂量。
Objective: To assess the effect of liver impairment on the pharmacokinetics of tolcapone and to derive appropriate dose recommendations for patients with this disease who are undergoing treatment for Parkinson's disease.Study design: In an open, two-way crossover study, 16 patients with moderate liver disease (eight with cirrhotic and eight with noncirrhotic liver disease) and eight healthy subjects received an oral dose of 200 mg tolcapone and an intravenous dose of 50 mg tolcapone on separate occasions. The concentrations of total and unbound tolcapone and its three major metabolites (tolcapone glucuronide, carboxylic acid, and 3-O-methyl metabolite) were assessed in plasma and urine.Results: On the basis of total drug concentration, the differences in tolcapone pharmacokinetics beta een the groups were small. However, lower clearance and volume of distribution of unbound drug were found among patients with cirrhosis than among control subjects. Plasma concentration of the pharmacologically inactive glucuronide metabolite was increased among patients with cirrhosis.Conclusions: Half of the recommended dosage of tolcapone should be administered to patients with cirrhosis of the liver to maintain the target steady-state concentration of unbound drug and to avoid accumulation of tolcapone glucuronide, Our data did not indicate a requirement for dosage adjustment in the presence of moderate chronic hepatitis.