Xceleron Ltd, The Biocentre, Innovation Way, York YO10 5NY, UK.
Eur J Pharm Sci. 2010 May 12;40(2):125-31. doi: 10.1016/j.ejps.2010.03.009. Epub 2010 Mar 20.
A human pharmacokinetic study was performed to assess the ability of a microdose to predict the pharmacokinetics of a therapeutic dose of fexofenadine and to determine its absolute oral bioavailability. Fexofenadine was chosen to represent an unmetabolized transporter substrate (P-gP and OATP). Fexofenadine was administered to 6 healthy male volunteers in a three way cross-over design. A microdose (100microg) of (14)C-drug was administered orally (period 1) and intravenously by 30min infusion (period 2). In period 3 an intravenous tracer dose (100microg) of (14)C-drug was administered simultaneously with an oral unlabelled therapeutic dose (120mg). Plasma was collected from all 3 periods and analysed for both total (14)C content and parent drug by accelerator mass spectrometry (AMS). For period 3, plasma samples were also analysed using HPLC-fluorescence to determine total drug concentration. Urine was collected and analysed for total (14)C. Good concordance between the microdose and therapeutic dose pharmacokinetics was observed. Microdose: CL 13L/h, CL(R) 4.1L/h, V(ss) 54L, t(1/2) 16h; therapeutic dose: CL 16L/h, CL(R) 6.2L/h, V(ss) 64L, t(1/2) 12h. The absolute oral bioavailability of fexofenadine was 0.35 (microdose 0.41, therapeutic dose 0.30). Despite a 1200-fold difference in dose of fexofenadine, the microdose predicted well the pharmacokinetic parameters following a therapeutic dose for this transporter dependent compound.
进行了一项人体药代动力学研究，以评估微剂量预测治疗剂量非索非那定药代动力学的能力，并确定其绝对口服生物利用度。选择非索非那定来代表未代谢的转运体底物（P-糖蛋白和有机阴离子转运多肽）。以三交叉设计给 6 名健康男性志愿者口服（第 1 期）和 30 分钟静脉输注（第 2 期）给予微剂量（100μg）（14）C-药物。在第 3 期，同时给予静脉示踪剂量（100μg）（14）C-药物和口服未标记治疗剂量（120mg）。从所有 3 个时期采集血浆，并通过加速质谱仪（AMS）分析总（14）C 含量和母体药物。对于第 3 期，还使用 HPLC-荧光法分析血浆样品以确定总药物浓度。收集尿液并分析总（14）C。观察到微剂量和治疗剂量药代动力学之间具有良好的一致性。微剂量：CL13L/h，CL（R）4.1L/h，V（ss）54L，t（1/2）16h；治疗剂量：CL16L/h，CL（R）6.2L/h，V（ss）64L，t（1/2）12h。非索非那定的绝对口服生物利用度为 0.35（微剂量 0.41，治疗剂量 0.30）。尽管非索非那定的剂量相差 1200 倍，但微剂量很好地预测了该转运体依赖性化合物治疗剂量后的药代动力学参数。
