Scheers Ellen, Leclercq Laurent, de Jong Jan, Bode Nini, Bockx Marc, Laenen Aline, Cuyckens Filip, Skee Donna, Murphy Joe, Sukbuntherng Juthamas, Mannens Geert
Pharmacokinetics, Dynamics and Metabolism, Janssen R&D, Beerse, Belgium (E.S., L.L., M.B., A.L., F.C., G.M.); Clinical Pharmacology, Janssen R&D, San Diego, California (J.d.J.); Pre-Clinical Project Development, Janssen R&D, Beerse, Belgium (N.B.); Clinical Pharmacology, Janssen R&D, Raritan, New Jersey (D.S., J.M.); and Pharmacyclics, Sunnyvale, California (J.S.).
Pharmacokinetics, Dynamics and Metabolism, Janssen R&D, Beerse, Belgium (E.S., L.L., M.B., A.L., F.C., G.M.); Clinical Pharmacology, Janssen R&D, San Diego, California (J.d.J.); Pre-Clinical Project Development, Janssen R&D, Beerse, Belgium (N.B.); Clinical Pharmacology, Janssen R&D, Raritan, New Jersey (D.S., J.M.); and Pharmacyclics, Sunnyvale, California (J.S.)
Drug Metab Dispos. 2015 Feb;43(2):289-97. doi: 10.1124/dmd.114.060061. Epub 2014 Dec 8.
The absorption, metabolism, and excretion of ibrutinib were investigated in healthy men after administration of a single oral dose of 140 mg of ¹⁴C-labeled ibrutinib. The mean (S.D.) cumulative excretion of radioactivity of the dose was 7.8% (1.4%) in urine and 80.6% (3.1%) in feces with <1% excreted as parent ibrutinib. Only oxidative metabolites and very limited parent compound were detected in feces, and this indicated that ibrutinib was completely absorbed from the gastrointestinal tract. Metabolism occurred via three major pathways (hydroxylation of the phenyl (M35), opening of the piperidine (M25 and M34), and epoxidation of the ethylene on the acryloyl moiety with further hydrolysis to dihydrodiol (PCI-45227, and M37). Additional metabolites were formed by combinations of the primary metabolic pathways or by further metabolism. In blood and plasma, a rapid initial decline in radioactivity was observed along with long terminal elimination half-life for total radioactivity. The maximum concentration (Cmax) and area under the concentration-time curve (AUC) for total radioactivity were higher in plasma compared with blood. The main circulating entities in blood and plasma were M21 (sulfate conjugate of a monooxidized metabolite on phenoxyphenyl), M25, M34, M37 (PCI-45227), and ibrutinib. At Cmax of radioactivity, 12% of total radioactivity was accounted for by covalent binding in human plasma. More than 50% of total plasma radioactivity was attributed to covalently bound material from 8 hours onward; as a result, covalent binding accounted for 38% and 51% of total radioactivity AUC(0-24 h) and AUC(0-72 h), respectively. No effect of CYP2D6 genotype was observed on ibrutinib metabolism. Ibrutinib was well-tolerated by healthy participants.
在健康男性单次口服140mg¹⁴C标记的依鲁替尼后，对其吸收、代谢和排泄情况进行了研究。该剂量放射性的平均（标准差）累积排泄率为：尿液中7.8%（1.4%），粪便中80.6%（3.1%），以依鲁替尼原形排泄的不到1%。在粪便中仅检测到氧化代谢物和极少量的母体化合物，这表明依鲁替尼从胃肠道完全吸收。代谢通过三条主要途径发生（苯基羟基化（M35）、哌啶开环（M25和M34）以及丙烯酰基部分乙烯的环氧化并进一步水解为二氢二醇（PCI - 45227和M37）。其他代谢物由主要代谢途径的组合或进一步代谢形成。在血液和血浆中，观察到放射性迅速初始下降以及总放射性的长末端消除半衰期。与血液相比，血浆中总放射性的最大浓度（Cmax）和浓度 - 时间曲线下面积（AUC）更高。血液和血浆中的主要循环物质为M21（苯氧基苯基单氧化代谢物的硫酸盐共轭物）、M25、M34、M37（PCI - 45227）和依鲁替尼。在放射性Cmax时，人血浆中共价结合占总放射性的12%。从8小时起，超过50%的总血浆放射性归因于共价结合物质；因此，共价结合分别占总放射性AUC(0 - 24 h)和AUC(0 - 72 h)的38%和51%。未观察到CYP2D6基因型对依鲁替尼代谢有影响。健康参与者对依鲁替尼耐受性良好。
