Department of Pharmacy, Faculty of Science, National University of Singapore, Block S7, Level 2, 18 Science Drive 4, Singapore 117543, Singapore.
Department of Pharmacy, Faculty of Science, National University of Singapore, Block S7, Level 2, 18 Science Drive 4, Singapore 117543, Singapore; School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China.
Eur J Pharm Sci. 2023 Aug 1;187:106475. doi: 10.1016/j.ejps.2023.106475. Epub 2023 May 22.
Cardiac cytochrome P450 2J2 (CYP2J2) metabolizes endogenous polyunsaturated fatty acid, arachidonic acid (AA), to bioactive regioisomeric epoxyeicosatrienoic acid (EET) metabolites. This endogenous metabolic pathway has been postulated to play a homeostatic role in cardiac electrophysiology. However, it is unknown if drugs that cause intermediate to high risk torsades de pointes (TdP) exhibit inhibitory effects against CYP2J2 metabolism of AA to EETs. In this study, we demonstrated that 11 out of 16 drugs screened with intermediate to high risk of TdP as defined by the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative are concurrently reversible inhibitors of CYP2J2 metabolism of AA, with unbound inhibitory constant (K) values ranging widely from 0.132 to 19.9 µM. To understand the physiological relevancy of K, the in vivo unbound drug concentration within human heart tissue (C) was calculated via experimental determination of in vitro unbound partition coefficient (K) for 10 CYP2J2 inhibitors using AC16 human ventricular cardiomyocytes as well as literature-derived values of fraction unbound in plasma (f) and plasma drug concentrations in clinical scenarios leading to TdP. Notably, all CYP2J2 inhibitors screened belonging to the high TdP risk category, namely vandetanib and bepridil, exhibited highest K values of 18.2 ± 1.39 and 7.48 ± 1.16 respectively although no clear relationship between C and risk of TdP could eventually be determined. R values based on basic models of reversible inhibition as per FDA guidelines were calculated using unbound plasma drug concentrations (C) and adapted using C which suggested that 4 out of 10 CYP2J2 inhibitors with intermediate to high risk of TdP demonstrate greatest potential for clinically relevant in vivo cardiac drug-AA interactions. Our results shed novel insights on the relevance of CYP2J2 inhibition in drugs with risk of TdP. Further studies ascertaining the role of CYP2J2 metabolism of AA in cardiac electrophysiology, characterizing inherent cardiac ion channel activities of drugs with risk of TdP as well as in vivo evidence of drug-AA interactions will be required prior to determining if CYP2J2 inhibition could be an alternative mechanism contributing to drug-induced TdP.
心脏细胞色素 P450 2J2（CYP2J2）代谢内源性多不饱和脂肪酸花生四烯酸（AA）为生物活性的差向异构型环氧二十碳三烯酸（EET）代谢物。该内源性代谢途径被认为在心电生理学中发挥着体内平衡的作用。然而，目前尚不清楚是否导致中度至高风险尖端扭转型室性心动过速（TdP）的药物对 CYP2J2 代谢 AA 至 EETs 具有抑制作用。在这项研究中，我们证明了在综合体外致心律失常试验（CiPA）倡议中被定义为具有中度至高 TdP 风险的 16 种药物中的 11 种同时是 CYP2J2 代谢 AA 的可逆抑制剂，未结合的抑制常数（K）值范围很广，从 0.132 到 19.9µM。为了理解 K 的生理相关性，我们通过使用 AC16 人心室肌细胞实验测定 10 种 CYP2J2 抑制剂的体外未结合分配系数（K），并利用文献中获得的血浆中未结合分数（f）和导致 TdP 的临床情况下的血浆药物浓度，计算了人心脏组织内的体内未结合药物浓度（C）。值得注意的是，所有被筛选出的属于高 TdP 风险类别的 CYP2J2 抑制剂，即凡德他尼和贝普地尔，表现出最高的 K 值，分别为 18.2±1.39 和 7.48±1.16，尽管最终无法确定 C 与 TdP 风险之间的明确关系。根据 FDA 指南，基于可逆抑制的基本模型计算了 R 值，并使用适应了 C 的 R 值，这表明在具有中度至高 TdP 风险的 10 种 CYP2J2 抑制剂中，有 4 种显示出最大的临床相关体内药物-AA 相互作用的潜力。我们的研究结果为 CYP2J2 抑制在具有 TdP 风险的药物中的相关性提供了新的见解。在确定 CYP2J2 抑制是否可能是导致药物引起的 TdP 的另一种机制之前，还需要进一步研究 AA 的 CYP2J2 代谢在心脏电生理学中的作用、表征具有 TdP 风险的药物的固有心脏离子通道活性以及体内药物-AA 相互作用的证据。
