Center for Drug Discovery, Department of Pathology & Immunology (X.Q., J.M.H., K.R.M., P.N., J.Z.G., S.P., M.M.M., F.L.), NMR and Drug Metabolism Core, Advanced Technology Cores (K.R.M., F.L.), Department of Pharmacology & Chemical Biology (K.R.M., J.W., M.M.M., F.L.), and Department of Molecular & Cellular Biology (S.Y.J., K.-D.B., F.L.), Baylor College of Medicine, Houston, Texas; Department of Pediatrics, Duke University Medical Center, Durham, North Carolina (M.B., K.-D.B.); Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (H.C., P.K.); and Division of Biochemical Toxicology, National Center for Toxicological Research/US Food and Drug Administration (FDA), Jefferson, Arkansas (S.C., L.G.).
Center for Drug Discovery, Department of Pathology & Immunology (X.Q., J.M.H., K.R.M., P.N., J.Z.G., S.P., M.M.M., F.L.), NMR and Drug Metabolism Core, Advanced Technology Cores (K.R.M., F.L.), Department of Pharmacology & Chemical Biology (K.R.M., J.W., M.M.M., F.L.), and Department of Molecular & Cellular Biology (S.Y.J., K.-D.B., F.L.), Baylor College of Medicine, Houston, Texas; Department of Pediatrics, Duke University Medical Center, Durham, North Carolina (M.B., K.-D.B.); Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (H.C., P.K.); and Division of Biochemical Toxicology, National Center for Toxicological Research/US Food and Drug Administration (FDA), Jefferson, Arkansas (S.C., L.G.)
Drug Metab Dispos. 2022 Feb;50(2):128-139. doi: 10.1124/dmd.121.000633. Epub 2021 Nov 16.
Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor, widely used for the treatment of major depressive disorder. Although DLX has shown good efficacy and safety, serious adverse effects (e.g., liver injury) have been reported. The mechanisms associated with DLX-induced toxicity remain elusive. Drug metabolism plays critical roles in drug safety and efficacy. However, the metabolic profile of DLX in mice is not available, although mice serve as commonly used animal models for mechanistic studies of drug-induced adverse effects. Our study revealed 39 DLX metabolites in human/mouse liver microsomes and mice. Of note, 13 metabolites are novel, including five -acetyl cysteine adducts and one reduced glutathione (GSH) adduct associated with DLX. Additionally, the species differences of certain metabolites were observed between human and mouse liver microsomes. CYP1A2 and CYP2D6 are primary enzymes responsible for the formation of DLX metabolites in liver microsomes, including DLX-GSH adducts. In summary, a total of 39 DLX metabolites were identified, and species differences were noticed in vitro. The roles of CYP450s in DLX metabolite formation were also verified using human recombinant cytochrome P450 (P450) enzymes and corresponding chemical inhibitors. Further studies are warranted to address the exact role of DLX metabolism in its adverse effects in vitro (e.g., human primary hepatocytes) and in vivo (e.g., Cyp1a2-null mice). SIGNIFICANCE STATEMENT: This current study systematically investigated Duloxetine (DLX) metabolism and bioactivation in liver microsomes and mice. This study provided a global view of DLX metabolism and bioactivation in liver microsomes and mice, which are very valuable to further elucidate the mechanistic study of DLX-related adverse effects and drug-drug interaction from metabolic aspects.
度洛西汀（DLX）是一种双重 5-羟色胺和去甲肾上腺素再摄取抑制剂，广泛用于治疗重度抑郁症。尽管 DLX 显示出良好的疗效和安全性，但已报道其严重的不良反应（如肝损伤）。与 DLX 诱导的毒性相关的机制仍不清楚。药物代谢在药物安全性和疗效中起着关键作用。然而，尽管小鼠被广泛用作药物引起的不良反应机制研究的常用动物模型，但 DLX 在小鼠中的代谢谱尚不清楚。我们的研究在人/鼠肝微粒体和小鼠中揭示了 39 种 DLX 代谢物。值得注意的是，有 13 种是新的代谢物，包括与 DLX 相关的 5 种乙酰半胱氨酸加合物和一种还原型谷胱甘肽（GSH）加合物。此外，还观察到人肝微粒体和鼠肝微粒体中某些代谢物的种属差异。CYP1A2 和 CYP2D6 是肝脏微粒体中形成 DLX 代谢物的主要酶，包括 DLX-GSH 加合物。总之，共鉴定出 39 种 DLX 代谢物，并在体外观察到种属差异。还使用人重组细胞色素 P450（P450）酶和相应的化学抑制剂验证了 CYP450 酶在 DLX 代谢物形成中的作用。需要进一步的研究来解决 DLX 代谢在其体外（例如，人原代肝细胞）和体内（例如，Cyp1a2 基因敲除小鼠）不良反应中的确切作用。意义陈述：本研究系统地研究了度洛西汀（DLX）在肝微粒体和小鼠中的代谢和生物活化。本研究提供了 DLX 在肝微粒体和小鼠中代谢和生物活化的全景图，这对于从代谢角度进一步阐明与 DLX 相关的不良反应和药物相互作用的机制研究非常有价值。
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