Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia.
School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
AAPS J. 2019 Jan 9;21(2):15. doi: 10.1208/s12248-018-0262-1.
The multi-kinase inhibitor sorafenib (SOR) is clinically important in the treatment of hepatocellular and renal cancers and undergoes CYP3A4-dependent oxidation in liver to the pharmacologically active N-oxide metabolite (SNO). There have been reports that kinase inhibitors such as SOR may precipitate pharmacokinetic interactions with coadministered drugs that compete for CYP3A4-mediated biotransformation, but these occur non-uniformly in patients. Clinical evidence also indicates that SNO accumulates in serum of some patients during prolonged SOR therapy. In this study undertaken in hepatic microsomes from individual donors, we assessed the possibility that SNO might contribute to pharmacokinetic interactions mediated by SOR. Enzyme kinetics of CYP3A4-mediated midazolam 1'-hydroxylation in individual human hepatic microsomes were analyzed by non-linear regression and appropriate replots. Thus, SNO and SOR were linear-mixed inhibitors of microsomal CYP3A4 activity (Ks 15 ± 4 and 33 ± 14 μM, respectively). To assess these findings, further molecular docking studies of SOR and SNO with the 1TQN crystal structure of CYP3A4 were undertaken. SNO elicited a larger number of interactions with key amino acid residues located in substrate recognition sequences of the enzyme. In the optimal docking pose, the N-oxide moiety of SNO was also found to interact directly with the heme moiety of CYP3A4. These findings suggest that SNO could contribute to pharmacokinetic interactions involving SOR, perhaps in individuals who produce high circulating concentrations of the metabolite.
多激酶抑制剂索拉非尼（SOR）在治疗肝癌和肾癌方面具有重要的临床意义，在肝脏中经 CYP3A4 依赖性氧化生成具有药理活性的 N-氧化物代谢物（SNO）。有报道称，像 SOR 这样的激酶抑制剂可能会与共同给予的药物发生药物动力学相互作用，这些药物竞争 CYP3A4 介导的生物转化，但这些相互作用在患者中并不均匀。临床证据还表明，在 SOR 治疗期间，一些患者的血清中 SNO 会积累。在这项在个体供体的肝微粒体中进行的研究中，我们评估了 SNO 可能导致 SOR 介导的药物动力学相互作用的可能性。通过非线性回归和适当的重绘图分析个体人肝微粒体中 CYP3A4 介导的咪达唑仑 1'-羟化的酶动力学。因此，SNO 和 SOR 是微粒体 CYP3A4 活性的线性混合抑制剂（Ks 分别为 15 ± 4 和 33 ± 14 μM）。为了评估这些发现，我们对 SOR 和 SNO 与 CYP3A4 的 1TQN 晶体结构进行了进一步的分子对接研究。SNO 与位于酶底物识别序列中的关键氨基酸残基产生了更多的相互作用。在最佳对接构象中，还发现 SNO 的 N-氧化物部分与 CYP3A4 的血红素部分直接相互作用。这些发现表明，SNO 可能会导致涉及 SOR 的药物动力学相互作用，也许在产生高循环代谢物浓度的个体中。
