贝沙罗汀软胶囊在复发难治性皮肤T细胞淋巴瘤患者中的药代动力学研究

Pharmacokinetics of bexarotene soft capsules in patients with relapsed or refractory cutaneous T-cell lymphoma

目的:评价贝沙罗汀在复发难治性皮肤T细胞淋巴瘤患者中的药物代谢动力学。方法:建立荧光液相色谱法,以乙腈、乙酸铵、乙酸等为流动相成分,在激发波长260 nm、发射波长430 nm的色谱条件下进行方法学考察及血药浓度测定。所得到的血药浓度以DAS 2.0药代动力学参数计算程序进行参数计算。皮肤T细胞淋巴瘤患者接受贝沙罗汀口服300 mg.m-2,qd,连用4周,进行单剂量和多剂量药代动力学分析。结果:建立的荧光液相色谱法在10～1 000 ng.mL-1之间线性关系良好(r=0.999 7),在空白血浆中20,100和800 ng.mL-1浓度的提取回收率分别为79.49%8,7.06%和78.56%。血药浓度测定结果显示,5例皮肤T-细胞淋巴瘤患者口服贝沙罗汀软胶囊300 mg.m-2,服药d 1和连续服药d 28的Cmax分别为366.31和652.44 ng.mL-1;Tmax分别为1.80和1.88 h;t1/2分别为2.56和3.18 h;AUC0～t分别为1 680.96和2 133.34ng.mL-1.h。结论:建立的荧光液相色谱法稳定,敏感性高。皮肤T-细胞淋巴瘤患者口服300 mg.m-2的贝沙罗汀软胶囊后吸收较快,连续服药d 28时峰浓度高于服药d 1时峰浓度近1倍,可见贝沙罗汀在受试者体内有一定的蓄积。

Objective： To evaluate the pharmacokinetics（PKs） of bexarotene in patients with relapsed or refractory early-and advanced-stage cutaneous T-cell lymphoma（CTCL）.Methods： We developed a liquid chromatographic method with fluorescence detector for determination of bexarotene in human plasma.The mobile phase was consisted of acetonitrile,acetic acid and ammonium acetate.The drug was analyzed with a fluorescence detector using an exciting wavelength at 260nm and an emission wavelength at 430nm.DAS 2.0 pharmacokinetic parameter program was used for calculation of parameters.Patients with refractory or relapsed CTCL were enrolled in this study.Bexarotene soft capsules（300mg·m-2） were administered orally,once daily,for 4 consecutive weeks.Results： A linearity was obtained in the range from 10 to 1000ng·mL-1 of bexarotene in plasma with a good correlation coefficient（r=0.9997）.The mean recoveries were 79.49%,87.06% and 78.56% for concentrations of 20,100 and 800ng·mL-1,respectively.Five patients with refractory or relapsed CTCL were enrolled in this study.Cmax of bexarotene at the 1st and 28th day were 366.31 and 652.44ng·mL-1,Tmax were 1.80 and 1.88h,t1/2 were 2.56 and 3.18h;and AUC0~t were 1680.96 and 2133.34ng·mL-1·h,respectively.Conclusion： The improved method is stable and sensitive.The analysis of PKs suggests that the absorption of bexarotene is rapid after multiple dose administration on a 300mg·m-2 orally once daily schedule.Plasma concentration is increased by nearly 1-fold after consecutive dosing for 28 days,indicating an accumulation.