Clinical Trial Center, Kitasato University East Hospital, Kanagawa, Japan.
J Clin Pharm Ther. 2010 Apr;35(2):169-75. doi: 10.1111/j.1365-2710.2009.01159.x.
Fexofenadine is a P-glycoprotein substrate of low bioavailability. It is primarily excreted into faeces as a parent drug via biliary excretion. The predictability from microdose data for the drug absorbed via transporters such as P-glycoprotein is not known. Therefore, this study assessed the predictability of therapeutic-dose pharmacokinetics of fexofenadine from microdosing data using non-radioisotope-labelled drug and liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS).
In a single dose, randomized, two-way crossover study, eight subjects received a microdose (100 microg) or a therapeutic dose (60 mg) of fexofenadine. Blood samples were collected until 12 h after dosing, and assayed using LC/MS/MS.
Plasma concentration-time curves of fexofenadine between microdose and therapeutic dose were similar. The mean +/- SD of C(max) normalized to 60 mg dose after microdose and therapeutic dose were 379 +/- 147 and 275 +/- 145 ng/mL respectively. The mean AUC(last) normalized to 60 mg dose after microdose and therapeutic dose were 1914 +/- 738 and 1431 +/- 432 ng/h/mL respectively. The mean dose-adjusted C(max) and AUC(last) after microdose were higher compared with those after therapeutic dose. Individual plots of C(max) and AUC(last) normalized to 60 mg dose, were similar for microdose and therapeutic dose. None of the pharmacokinetic parameters were statistically different using anova. Overall, the microdose pharmacokinetics profile was similar to, and hence predictive of, that of the therapeutic dose.
For the P-glycoprotein substrate fexofenadine, the predictability of therapeutic-dose pharmacokinetics from microdose data was good. A microdose study using a non-radioisotope-labelled drug and LC/MS/MS is convenient, and has the potential to aid the early selection of drug candidates.
非索非那定是一种低生物利用度的 P-糖蛋白底物。它主要通过胆汁排泄以母体药物的形式从粪便中排泄。通过转运体（如 P-糖蛋白）吸收的药物，从微剂量数据预测其治疗剂量药代动力学的可预测性尚不清楚。因此，本研究采用非放射性标记药物和液相色谱/电喷雾串联质谱（LC/ESI-MS/MS），从微剂量数据评估非索非那定治疗剂量药代动力学的可预测性。
在一项单次、随机、双交叉研究中，8 名受试者分别接受了 100μg 的微剂量或 60mg 的治疗剂量非索非那定。在给药后 12 小时内采集血样，并使用 LC/MS/MS 进行检测。
微剂量和治疗剂量下非索非那定的血药浓度-时间曲线相似。微剂量和治疗剂量后归一化为 60mg 剂量的 Cmax 的平均值±标准差分别为 379±147 和 275±145ng/mL。微剂量和治疗剂量后归一化为 60mg 剂量的 AUC(last)的平均值±标准差分别为 1914±738 和 1431±432ng/h/mL。微剂量后归一化为 60mg 剂量的平均剂量调整的 Cmax 和 AUC(last)均高于治疗剂量后。微剂量和治疗剂量的 Cmax 和 AUC(last)的个体标绘图相似。使用方差分析，所有药代动力学参数均无统计学差异。总体而言，微剂量药代动力学特征与治疗剂量相似，因此可以预测治疗剂量。
对于 P-糖蛋白底物非索非那定，从微剂量数据预测治疗剂量药代动力学的可预测性良好。使用非放射性标记药物和 LC/MS/MS 的微剂量研究既方便又具有潜在优势，可以辅助早期选择候选药物。
