Loi C M, Alvey C W, Vassos A B, Randinitis E J, Sedman A J, Koup J R
Department of Pharmacokinetics, Dynamics, and Metabolism, Parke-Davis Pharmaceutical Research Division, Ann Arbor, MI 48105, USA.
J Clin Pharmacol. 1999 Sep;39(9):920-6. doi: 10.1177/00912709922008533.
This study evaluated the steady-state pharmacokinetics and dose proportionality of troglitazone, metabolite 1 (sulfate conjugate), and metabolite 3 (quinone metabolite) following administration of daily oral doses of 200, 400, and 600 mg troglitazone for 7 days (per dosing period) to 21 subjects. During each dosing period, plasma samples were collected predose on days 1, 5, 6 and 7 and serially for 24 hours on day 7. Steady-state plasma concentrations for troglitazone, metabolite 1, and metabolite 3 were achieved by day 7. Troglitazone was rapidly absorbed with mean tmax values of 2.7 to 2.9 hours. Mean Cmax and AUC(0-24) values for troglitazone, metabolite 1, and metabolite 3 increased proportionally with increasing troglitazone doses over the clinical dose range of 200 mg to 600 mg administered once daily. Mean troglitazone CL/F, percent fluctuation, and AUC ratios of metabolite 1 and metabolite 3 to troglitazone were similar across dose groups. These data suggest that the pharmacokinetics and disposition of troglitazone and its metabolites are independent of dose over the dose range studied. Thus, troglitazone, metabolite 1, and metabolite 3 displayed linear pharmacokinetics at steady-state.
本研究评估了21名受试者每日口服200、400和600毫克曲格列酮，持续7天（每个给药周期）后，曲格列酮、代谢物1（硫酸结合物）和代谢物3（醌代谢物）的稳态药代动力学及剂量比例关系。在每个给药周期内，于第1、5、6和7天给药前采集血浆样本，并在第7天连续采集24小时的样本。到第7天时，曲格列酮、代谢物1和代谢物3达到了稳态血浆浓度。曲格列酮吸收迅速，平均达峰时间为2.7至2.9小时。在每日一次给予200毫克至600毫克的临床剂量范围内，曲格列酮、代谢物1和代谢物3的平均峰浓度和药时曲线下面积（0 - 24）值随曲格列酮剂量增加成比例增加。各剂量组曲格列酮的平均清除率/表观分布容积、波动百分比以及代谢物1和代谢物3与曲格列酮的药时曲线下面积比值相似。这些数据表明，在所研究的剂量范围内，曲格列酮及其代谢物的药代动力学和处置情况与剂量无关。因此，曲格列酮、代谢物1和代谢物3在稳态时呈现线性药代动力学。
