State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, CAS Key Laboratory of Chemistry of Plant Resources in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China.
University of Chinese Academy of Sciences, No. 19 (A) Yuquan Road, Shijingshan District, Beijing 100049, China.
Molecules. 2024 Sep 12;29(18):4324. doi: 10.3390/molecules29184324.
Cardiovascular disease is the first cause of death worldwide and kills more people each year than any other cause of death. N, N-dimethylaniline-heliamine (DH), a synthetic tetrahydroisoquinoline alkaloid, has shown notable antiarrhythmic activity. However, the metabolic processes and pharmacokinetic characteristics of DH in rats have not been studied. This study aims to identify its metabolites, as well as develop and validate a rapid and efficient bioanalytical method for quantifying DH in rat plasma over a wide range of concentrations. Its metabolites were characterized in silico, in vitro, and in vivo. A series of 16 metabolites were identified, of which 12 were phase I metabolites and 4 were phase II metabolites. A low probability of DH binding to DNA, protein, and glutathione is predicted by the in silico model. The main metabolic processes of DH were demethylation, dehydrogenation, glucuronidation, and sulfation. Concentration-time profiles were generated by analyzing the plasma, and the outcomes were analyzed via non-compartmental analysis to identify the pharmacokinetic parameters. Among the detected parameters were the volume of distribution, estimated at 126,728.09 ± 56,867.09 mL/kg, clearance at 30,148.65 ± 15,354.27 mL/h/kg, and absolute oral bioavailability at 16.11%. The plasma distribution volume of DH was substantially higher than the overall plasma volume of rats, which suggests that DH has a specific tissue distribution in rats. This study suggests that DH is appropriately bioavailable and excreted via a variety of routes and has low toxicity.
心血管疾病是全球首要死因，每年导致的死亡人数超过其他任何死因。N，N-二甲基苯胺-海利胺（DH）是一种合成的四氢异喹啉生物碱，具有显著的抗心律失常活性。然而，DH 在大鼠体内的代谢过程和药代动力学特征尚未得到研究。本研究旨在鉴定其代谢物，并开发和验证一种用于定量测定大鼠血浆中 DH 的快速高效的生物分析方法，该方法可在广泛的浓度范围内使用。通过体内、体外和计算机模拟对其代谢物进行了表征。共鉴定出 16 种代谢物，其中 12 种为 I 相代谢物，4 种为 II 相代谢物。计算机模型预测 DH 与 DNA、蛋白质和谷胱甘肽结合的可能性较低。DH 的主要代谢途径为去甲基化、脱氢、葡萄糖醛酸化和硫酸化。通过分析血浆生成浓度-时间曲线，并通过非房室分析对结果进行分析，以确定药代动力学参数。检测到的参数包括分布容积，估计为 126728.09±56867.09mL/kg；清除率，估计为 30148.65±15354.27mL/h/kg；绝对口服生物利用度，估计为 16.11%。DH 的血浆分布容积明显高于大鼠的总体血浆容积，这表明 DH 在大鼠中有特定的组织分布。本研究表明，DH 具有适当的生物利用度，并通过多种途径排泄，且毒性较低。
