基于药动学及代谢物组学研究多柔比星在大鼠体内的心脏毒性

Metabolomics and Pharmacokinetics Study on the Cardiotoxicity of Doxorubicin in Rat

关键词:  多柔比星  多柔比星醇  心脏毒性  药动学  代谢物组学

Key words:  doxorubicin  doxorubicinol  cardiotoxicity  pharmacokinetics  metabolomics

摘要:

目的 测定多柔比星大剂量给药后原型药物及代谢产物的药动学特征及组织分布，以明确代谢产物在多柔比星急性心脏毒性中的作用。方法 测定多柔比星血清及心脏组织源性代谢物的变化特点，寻找与心脏毒性发生相关的代谢生物标志物及心脏毒性的潜在机制。利用LC-MS/MS测定多柔比星及多柔比星醇的浓度，利用GC-MS进行血清及心脏组织的代谢物组学分析。结果 多柔比星大鼠体内单剂量给药后，在心脏组织呈现高分布，且高剂量（10 mg·kg^-1）时分布显著增加。多柔比星醇的代谢转换率很低，且在心脏组织中的分布较低。代谢物组学研究结果表明，小分子能量物质酮体及脂肪酸为血清样本中的主要差异性物质。心脏组织中主要差异性物质为脂肪酸和甘油单酯。结论 多柔比星单剂量给药后，其在心脏中分布较高，且高剂量时特异性分布增加。多柔比星醇在血清及心脏组织中的浓度较低，推测其在急性毒性中的作用有限。多柔比星单剂量给药会引起心脏组织内的以脂质代谢为主的能量代谢异常，能量代谢对多柔比星相关的急性心肌毒性具有重要作用。

Abstract:

OBJECTIVE To investigate the doxorubicin pharmacokinetics and metabolomics to give a clear idea of which substances are related with the toxicity and to find potential cardiotoxicity related biomarkers and explanation of mechanism of systematical toxicity induced by doxorubicin. METHODS Rat was treated by doxorubicin and cardiac toxicity was denoted. The pharmacokinetics of doxorubicin and doxorubicinol was study by LC-MS/MS. Rats serum and heart tissue samples were obtained and subjected to GC-MS analysis to find potential biomarkers and mechanisms of cardiotoxicity. RESULTS Pharmacokinetics study revealed the lower concentration of the secondary alcohol metabolites in serum and heart. Metabolomics analysis show that the metabolic profiling distinguished doxorubicin group from the control group and potential biomarkers such as ketone body, fatty acids and monoacylglycerols are identified. CONCLUSION Pharmacokinetics study reveal the high concentration of doxorubicin in heart with nonlinear dynamics doxorubicinol could not be the key toxicant for low concentrations in vivo in the doxorubicin's cardiotoxicity. Metabolomic analysis of serum and heart revealed the complementary evidence of alterations in fatty acid biosynthesis, lipid metabolism and ketone body metabolite after doxorubicin treatment.