肿瘤患者单次和多次口服替吉奥片的药动学研究

朱仲玲; 薛津怀; 阎昭; 朱莉; 刘美君

doi:10.3969/j.issn.1000-8179.2011.10.016

摘要: 目的：评价肿瘤患者单次和多次口服替吉奥片的药动学特征。方法：设单次给药组10例，给药剂量60 mg；连续给药组9例，每次给药剂量60 mg， 1日2次，连续服用7 d。采用液相色谱-串联质谱法测定血浆中替加氟及其代谢物5-氟脲嘧啶（5-FU）、吉美嘧啶（CDHP）和奥替拉西（Oxo）的浓度。采用DAS2.0药动学软件进行药动学参数的分析和计算。结果：单次给药替加氟Cmax为（1407±383）ng·mL-1，AUC0-t为（15 403±8439） ng·h·mL-1，活性代谢物5-氟脲嘧啶Cmax为（128±36） ng·mL-1， AUC0-t为（539±138） ng· h· mL-1，吉美嘧啶Cmax为（222±93） ng· mL-1， AUC0-t为（962±390） ng· h· mL-1，奥替拉西Cmax为（33.2±14.6） ng· mL-1， AUC0-t为（117±64） ng·h·mL-1。与单次给药相比，多次给药后替加氟的Cmax和AUC增加明显（P<0.05），但其增加程度与理论蓄积系数接近，而代谢物氟脲嘧啶、吉美嘧啶及奥替拉西的Cmax和AUC无明显增加。受试者在研究期间未出现重度以上不良反应。结论：口服替吉奥片后，受试者耐受良好。多次给药后，替吉奥片主要成分的药代动力学行为没有发生明显变化。

Abstract: Single-Dose and Multiple-Dose Pharmacokinetic Study of Tegafur, Gimeracil, and OteracilPotassium Tablets in Patients with Advanced Solid TumorsZhongling ZHU1, Jinhuai XUE1, Zhao YAN1, Li ZHU2, Meijun LIU1Correspondence to: Zhao YAN, E-mail: yanzhaotj@126.com1Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China2Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, ChinaAbstract Objective: To study the single-dose and multiple-dose pharmacokinetics of tegafur, gimeracil, and oteracil potassiumtablets in patients with advanced solid tumors. Methods: Ten patients for the single-dose pharmacokinetics study were administrated 60mg of tegafur, gimeracil, and oteracil potassium tablets. Nine patients for the multiple-dose pharmacokinetics study were given 60 mgof tegafur, gimeracil, and oteracil potassium tablets twice a day for seven consecutive days. The plasma concentrations of tegafur, 5-flu-orouracil ( 5-FU ), gimeracil ( CDHP ), and oteracil potassium ( Oxo ) were determined using high-performance liquid chromatogra-phy-tandem mass spectrometry. DAS 2.0 was applied to assess the plasma concentration-time data. Results: After single-dose adminis-tration, the Cmax and AUC0-t of tegafur were ( 1407 ± 383 ) ng·mL-1and ( 15403 ± 8439 ) ng·h·mL-1; for 5-FU, ( 128 ± 36 ) ng·mL-1and ( 539 ± 138 ) ng·h·mL-1; for CDHP, ( 222 ± 93 ) ng·mL-1and ( 962 ± 390 ) ng·h·ml-1, and for Oxo, ( 33.2 ± 14.6 ) ng·mL-1and (117 ± 64 ) ng·h·mL-1. Comparing single-dose group with multiple-dose group, no significant differences were observed in the pharma-cokinetics parameters of 5-FU, CDHP, and Oxo. With respect to tegafur, significant differences were observed in Cmax and AUC, butthe increase in Cmax and AUC were close to accumulation coefficient. The toxicity of tegafur, gimeracil, and oteracil potassium tabletsvaried from mild to moderate. Grades 3 or 4 toxicity was not observed during the study. Conclusion: All participants had good toler-ance throughout the study. After seven days of continuous administration, no significant differences were observed in the pharmacoki-netic parameters of tegafur, 5-FU, CDHP, and Oxo.Keywords Tegafur; LC/MS/MS; Pharmacokinetics; Neoplasm