Uno Tsukasa, Shimizu Mikiko, Sugawara Kazunobu, Tateishi Tomonori
Department of Clinical Pharmacology, Hirosaki University School of Medicine, Hirosaki, Japan.
Drug Metab Dispos. 2006 Nov;34(11):1875-9. doi: 10.1124/dmd.106.011023. Epub 2006 Aug 23.
The aim of this study was to determine the inhibitory effect of itraconazole at different coadministered doses on fexofenadine pharmacokinetics. In a randomized four-phase crossover study, 11 healthy volunteers were administered a 60-mg fexofenadine hydrochloride tablet alone on one occasion (control phase) and with three different doses of 50, 100, and 200 mg of itraconazole simultaneously on the other three occasions (itraconazole phase). Although the elimination half-life and the renal clearance of fexofenadine remained relatively constant, a single administration of itraconazole with fexofenadine significantly increased mean area under the plasma concentration-time curve (AUC(0-infinity)) of fexofenadine (1701/3554, 4308, and 4107 ng h/ml for control; 50 mg, 100 mg, and 200 mg of itraconazole, respectively). Although mean itraconazole AUC(0-48) from 50 mg to 200 mg increased dose dependently from 214 to 772 ng h/ml (p = 0.003), no significant difference was noted in the three parameters, AUC (p = 0.423), C(max) (p = 0.636), and renal clearance (p = 0.495), of fexofenadine among the three doses of itraconazole. Itraconazole exposure at a lower dose (50 mg) compared with the clinical dose (200 mg once or twice daily) had the maximal effect on fexofenadine pharmacokinetics, even though itraconazole plasma concentrations gradually increased after higher doses. These findings suggest that the interaction may occur at the gut wall before reaching the portal vein circulation, and the inhibitory effect must be saturated by substantial local concentrations of itraconazole in the gut lumen after 50-mg dosing.
本研究的目的是确定不同合用剂量的伊曲康唑对非索非那定药代动力学的抑制作用。在一项随机四阶段交叉研究中，11名健康志愿者在一个给药周期单独服用60 mg盐酸非索非那定片（对照期），在另外三个给药周期同时服用三种不同剂量（50、100和200 mg）的伊曲康唑（伊曲康唑期）。尽管非索非那定的消除半衰期和肾清除率保持相对恒定，但伊曲康唑与非索非那定单次合用显著增加了非索非那定的血浆浓度-时间曲线下平均面积（AUC(0-∞)）（对照期为1701/3554、4308和4107 ng·h/ml；伊曲康唑50 mg、100 mg和200 mg时分别为上述值）。尽管伊曲康唑从50 mg至200 mg的平均AUC(0-48)随剂量增加从214 ng·h/ml增至772 ng·h/ml（p = 0.003），但三种剂量伊曲康唑合用下非索非那定的三个参数，即AUC（p = 0.423）、C(max)（p = 0.636）和肾清除率（p = 0.495），均未观察到显著差异。与临床剂量（每日一次或两次200 mg）相比，较低剂量（50 mg）的伊曲康唑暴露对非索非那定药代动力学的影响最大，尽管较高剂量后伊曲康唑血浆浓度逐渐升高。这些发现表明，相互作用可能在到达门静脉循环之前在肠壁发生，且50 mg给药后肠腔内大量局部浓度的伊曲康唑必须使抑制作用饱和。
