Pharmacokinetics of Darolutamide in Mouse - Assessment of the Disposition of the Diastereomers, Key Active Metabolite and Interconversion Phenomenon: Implications to Cancer Patients.

Drug metabolism letters Pub Date : 2021-01-01 DOI:10.2174/1872312814666200521091236

Neeraj K Saini, Bhavesh B Gabani, Umesh Todmal, Suresh P Sulochana, Vinay Kiran, Mohd Zainuddin, Narayanan Balaji, Sai B Polina, Nuggehally R Srinivas, Ramesh Mullangi

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引用次数: 3

Abstract

Background: Darolutamide is recently approved for the treatment of non-metastatic castrate resistance prostate cancer. Hitherto, no stereoselective pharmacokinetic data have been published pertaining to darolutamide and its diastereomers in animals or humans. The key aims of the experiment were to examine darolutamide, S,S-darolutamide and S,R-darolutamide with respect to (a) assessment of in vitro metabolic stability and protein binding and (b) characterization of in vivo oral and intravenous pharmacokinetics in mice.

Methods: In vitro (liver microsomes stability and protein binding) and in vivo experiments (oral/intravenous dosing to mice) were carried out using darolutamide, S,S-darolutamide and S,Rdarolutamide. Besides, tissue levels of darolutamide, S,S-darolutamide and S,R-darolutamide were measured following oral and intravenous dosing. Appropriate plasma/tissue samples served to determine the pharmacokinetics of various analytes in mice. Liquid chromatography in tandem with mass spectrometry procedures enabled the delineation of the plasma pharmacokinetics, in vitro and tissue uptake data of the various analytes.

Results: Chiral inversion was absent in the metabolic stability study. However, darolutamide showed profound stereoselectivity (S,S-darolutamide greater than S,R-darolutamide) after either intravenous or oral dosing. S,R-darolutamide but not S,S-darolutamide showed conversion to its antipode post oral and intravenous dosing to mice. Regardless of oral or intravenous dosing, active keto darolutamide formation was evident after administration of darolutamide, S,S-darolutamide or S,R- darolutamide. Tissue data supported the observations in plasma; however, tissue exposure of darolutamide, S,Sdarolutamide and S,R-darolutamide was much lower as compared to plasma.

Conclusion: In lieu of the human pharmacokinetic data, although the administration of diastereomeric darolutamide was justified, it is proposed to delineate the clinical pharmacokinetics of S,Rdarolutamide and S,S-darolutamide relative to darolutamide in future clinical pharmacology studies.

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达罗卢胺在小鼠体内的药代动力学——非对映体、关键活性代谢物和相互转化现象的分布评估:对癌症患者的影响。

背景:Darolutamide最近被批准用于治疗非转移性去势抵抗性前列腺癌。迄今为止，还没有发表关于达罗卢胺及其非对映体在动物或人类中的立体选择性药代动力学数据。实验的主要目的是研究darolutamide, S,S-darolutamide和S,R-darolutamide在(a)体外代谢稳定性和蛋白质结合的评估以及(b)小鼠体内口服和静脉内药代动力学的表征。方法:采用darolutamide, S,S-darolutamide和S,Rdarolutamide进行体外(肝微粒体稳定性和蛋白质结合)和体内(小鼠口服/静脉给药)实验。此外，在口服和静脉给药后，测量组织中达罗他胺、S、S-达罗他胺和S、r -达罗他胺的水平。适当的血浆/组织样品用于测定各种分析物在小鼠体内的药代动力学。液相色谱联用质谱法可以描述各种分析物的血浆药代动力学、体外和组织吸收数据。结果:代谢稳定性研究中无手性反转。然而，静脉或口服给药后，darolutamide显示出深刻的立体选择性(S,S-darolutamide大于S,R-darolutamide)。S,R-darolutamide在小鼠口服和静脉给药后转化为对映体，而S,S-darolutamide不转化为对映体。无论口服或静脉给药，在服用达罗他胺、S、S-达罗他胺或S、R-达罗他胺后，活性酮类达罗他胺形成明显。组织数据支持血浆中的观察结果;然而，与血浆相比，darolutamide, S,Sdarolutamide和S,R-darolutamide的组织暴露要低得多。结论:代替人体药代动力学数据，尽管非对异构体达罗卢胺的施用是合理的，但建议在未来的临床药理学研究中描述S,Rdarolutamide和S,S-darolutamide相对于达罗卢胺的临床药代动力学。

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Drug metabolism letters Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

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期刊介绍： Drug Metabolism Letters publishes letters and research articles on major advances in all areas of drug metabolism and disposition. The emphasis is on publishing quality papers very rapidly by taking full advantage of the Internet technology both for the submission and review of manuscripts. The journal covers the following areas: In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites.