Pharmacokinetics and Brain Distribution and Metabolite Identification of Coptisine, a Protoberberine Alkaloid with Therapeutic Potential for CNS Disorders, in Rats
Pharmacokinetics and Brain Distribution and Metabolite Identification of Coptisine, a Protoberberine Alkaloid with Therapeutic Potential for CNS Disorders, in Rats
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黄连碱（一种对中枢神经系统疾病具有治疗潜力的原小檗碱生物碱）在大鼠体内的药代动力学、脑分布和代谢物鉴定
DOI：
10.1248/bpb.b15-00293
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发表时间：
2015-10-01
影响因子：
2
通讯作者：
Ma, Shuangeheng
中科院分区：
文献类型：
--
作者：
Su, Jin;Miao, Qing;Ma, Shuangeheng
黄连碱（Coptisine，COP）是一种来源于小檗科等中草药的原小檗碱生物碱（protoberberine alkaloid，PBA），具有改善中枢神经系统疾病的作用。然而，其药代动力学、处置和代谢尚不明确。建立了液相色谱-串联质谱（LC-MS/MS）分析生物样品中COP的方法。为了更好地了解其体内药理学活性，测定了口服（50 mg/kg）和静脉给药（10 mg/kg）后大鼠血浆中的COP浓度。对于脑分布研究，在以10 mg/kg静脉给药后，检查了5个不同区域中的COP浓度。通过非房室分析计算血浆和脑中COP浓度-时间曲线的药代动力学参数以及脑-血浆系数（K-p，K-脑）。还鉴定了COP在大鼠体内和体外（尿液、胆汁、肝微粒体和肠道细菌孵育）的代谢产物。首次鉴定了17种代谢产物，包括11种通过羟基化、氢化、去甲基化、脱氢、去甲基化形成的非结合代谢产物和6种葡糖苷酸和硫酸盐结合物。结果表明，COP在大鼠体内的口服生物利用度较低（8.9%），血浆半衰期较短（T-1/2=0.71 h）。静脉给药后，它迅速穿过血脑屏障，以更高的浓度积累，然后从不同的脑区域缓慢消除。此外，COP在体内和体外通过多种代谢途径转化为代谢产物。这些结果有助于促进COP的进一步研究，并有助于阐明PBAs的代谢途径。
Coptisine (COP), a protoberberine alkaloid (PBA) from Chinese medicinal plants (such as family Berberidaceae), may be useful for improving central nervous system disorders. However, its pharmacokinetics, disposition and metabolism are not well defined. In the present study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for the analysis of COP in biological samples. To better understand its in vivo pharmacological activities, COP concentrations in rat plasma were determined after oral (50 mg/kg) and intravenous administration (10 mg/kg). For the brain distribution study, the concentration of COP in five different regions was examined after intravenous administration at 10 mg/kg. Pharmacokinetic parameters from the COP concentration-time profiles in plasma and brain, and the brain-to-plasma coefficient (K-p,K- brain) were calculated by non-compartmental analysis. The metabolites of COP in rats in vivo and in vitro (urine, bile, liver microsomes and intestinal bacteria incubation) were also identified. Seventeen metabolites, including 11 unconjugated metabolites formed by hydroxylation, hydrogenation, demethylation, dehydrogenation, demethylation, and 6 glucuronide and sulfate conjugates were identified for the first time. The results suggested that COP had low oral bioavailability of 8.9% and a short (plasma) half-life (T-1/2=0.71 h) in rats. After intravenous administration, it quickly crossed the blood-brain barrier, accumulating at higher concentrations and then was slowly eliminated from different brain regions. Moreover, COP was transformed into metabolites through multiple metabolic pathways in vivo and in vitro. These results should help to promote further research on COP and contribute to clarifying the metabolic pathways of PBAs.