Department of Pharmaceutics, University of Washington School of Pharmacy, Seattle, Washington, USA.
Clin Pharmacol Ther. 2011 Jun;89(6):888-95. doi: 10.1038/clpt.2011.53. Epub 2011 Apr 13.
An endogenous probe for CYP3A activity would be useful for early identification of in vivo cytochrome P450 (CYP) 3A4 inhibitors. The aim of this study was to determine whether formation clearance (CL(f)) of the sum of 6β-hydroxycortisol and 6β-hydroxycortisone is a useful probe of CYP3A4 inhibition in vivo. In human liver microsomes (HLMs), the formation of 6β-hydroxycortisol and 6β-hydroxycortisone was catalyzed by CYP3A4, and itraconazole inhibited these reactions with half maximal inhibitory concentration (IC(50))(,u) values of 3.1 nmol/l and 3.4 nmol/l, respectively. The in vivo IC(50,u) value of itraconazole for the combined CL(f) of 6β-hydroxycortisone and 6β-hydroxycortisol was 1.6 nmol/l. The greater inhibitory potency in vivo is probably due to circulating inhibitory itraconazole metabolites. The maximum in vivo inhibition was 59%, suggesting that f(m,CYP3A4) for cortisol and cortisone 6β-hydroxylation is ~60%. Given the significant decrease in CL(f) of 6β-hydroxycortisone and 6β-hydroxycortisol after 200-mg and 400-mg single doses of itraconazole, this endogenous probe can be used to detect moderate and potent CYP3A4 inhibition in vivo.
内源性探针 CYP3A 活性将有助于早期鉴定体内细胞色素 P450（CYP）3A4 抑制剂。本研究旨在确定 6β-羟基皮质醇和 6β-羟基皮质酮的总形成清除率（CL(f)）是否是体内 CYP3A4 抑制的有用探针。在人肝微粒体（HLM）中，6β-羟基皮质醇和 6β-羟基皮质酮的形成由 CYP3A4 催化，酮康唑分别以半最大抑制浓度（IC（50））（，u）值 3.1 nmol/l 和 3.4 nmol/l 抑制这些反应。酮康唑对 6β-羟基皮质酮和 6β-羟基皮质醇总 CL(f)的体内 IC（50，u）值为 1.6 nmol/l。体内更大的抑制效力可能是由于循环抑制酮康唑代谢物。最大体内抑制率为 59%，表明皮质醇和皮质酮 6β-羟化的 f(m,CYP3A4)约为 60%。鉴于酮康唑 200mg 和 400mg 单剂量后 6β-羟基皮质醇和 6β-羟基皮质酮的 CL(f)显著下降，这种内源性探针可用于检测体内中度和强效 CYP3A4 抑制。
