Templeton I E, Thummel K E, Kharasch E D, Kunze K L, Hoffer C, Nelson W L, Isoherranen N
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA.
Clin Pharmacol Ther. 2008 Jan;83(1):77-85. doi: 10.1038/sj.clpt.6100230. Epub 2007 May 9.
Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.
伊曲康唑（ITZ）在体外代谢为三种抑制性代谢产物：羟基伊曲康唑（OH-ITZ）、酮基伊曲康唑（keto-ITZ）和N-去烷基伊曲康唑（ND-ITZ）。本研究的目的是确定这些代谢产物对ITZ引起的药物相互作用的贡献。六名健康志愿者口服100 mg ITZ，持续7天，并在研究的第1天和第7天进行药代动力学分析。利用这些数据预测了ITZ及其代谢产物对CYP3A4的抑制程度。在所有志愿者的血浆样本中均检测到了ITZ、OH-ITZ、keto-ITZ和ND-ITZ。利用ITZ、OH-ITZ、keto-ITZ和ND-ITZ的平均非结合稳态浓度（C(ss,ave,u)）和肝微粒体抑制常数，预测了CYP3A4底物肝内在清除率下降3.9倍。与仅考虑ITZ暴露相比，考虑ITZ的循环代谢产物显著改善了CYP3A4抑制从体外到体内的外推。
