Pharmacokinetics and Excretion of Berberine and Its Nine Metabolites in Rats.
Pharmacokinetics and Excretion of Berberine and Its Nine Metabolites in Rats.
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小檗碱及其九种代谢物在大鼠体内的药代动力学和排泄
DOI：
10.3389/fphar.2020.594852
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发表时间：
2020
影响因子：
5.6
通讯作者：
Qiu F
中科院分区：
文献类型：
--
作者：
Feng X;Wang K;Cao S;Ding L;Qiu F
小檗碱是一种著名的生物碱，具有多种药理活性。以往的研究表明，小檗碱可以广泛代谢，代谢产物也有助于其治疗作用。然而，对于小檗碱的代谢产物，尤其是II相代谢产物，其药代动力学和排泄研究却鲜有报道。本研究的目的是全面研究小檗碱及其9种代谢产物的药代动力学和排泄特征，即小檗红碱（M1）、去亚甲基小檗碱（M2）、药根碱（M3）、药根碱-3-O-β-D-葡萄糖醛酸苷（M4）、药根碱-3-O-硫酸盐（M5）、沙芬地定-10-O-β-D-葡萄糖醛酸苷（M6）、小檗红碱-9-O-β-D-葡萄糖醛酸苷（M7）、去甲小檗碱-2-O-硫酸盐（M8）和去甲小檗碱-2-O-β-D-葡萄糖醛酸苷（M9）。建立了一种准确可靠的LC-MS/MS测定大鼠体内小檗碱及其9种代谢产物的方法。大鼠单次静脉注射（4.0 mg/kg）和口服（48.2、120和240 mg/kg）小檗碱后，获得了小檗碱及其9种代谢产物的药代动力学曲线。对于排泄研究，大鼠单次灌胃给予48.2 mg/kg小檗碱。结果表明，小檗碱在体内代谢迅速，9种代谢产物均能被检测到。小檗碱的绝对生物利用度为0.37 ± 0.11%。对于AUC 0 -48 h值，II相代谢产物远高于I相代谢产物，表明II相代谢产物是血液循环中存在的主要代谢产物。18.6%的小檗碱以小檗红碱（M1）的形式经粪便排出。盐酸小檗碱及其9种代谢产物在尿、胆汁和粪便中的总回收率为41.2%。本文首次系统研究了小檗碱及其9种代谢产物的药代动力学和排泄规律，为深入了解小檗碱的临床疗效和进一步开发奠定了基础。
Berberine, a well-known alkaloid, has been proved to possess various pharmacological activities. Previous studies demonstrated that berberine could be extensively metabolized and the metabolites also contributed to its therapeutic effects. However, as for berberine’s metabolites, especially phase II metabolites, pharmacokinetics and excretion studies were rarely reported. The objective of this study was to thoroughly investigate the pharmacokinetic and excretion profiles of berberine and its nine metabolites, namely, berberrubine (M1), demethyleneberberine (M2), jatrorrhizine (M3), jatrorrhizine-3-O-β-D-glucuronide (M4), jatrorrhizine-3-O-sulfate (M5), thalfendine-10-O-β-D-glucuronide (M6), berberrubine-9-O-β-D-glucuronide (M7), demethyleneberberine-2-O-sulfate (M8) and demethyleneberberine-2-O-β-D-glucuronide (M9) in rats. An accurate and reliable LC-MS/MS method was developed and validated for the determination of berberine and its nine metabolites in rat biosamples. Pharmacokinetic profiles of berberine and its nine metabolites were obtained after a single intravenous administration (4.0 mg/kg) and oral administration (48.2, 120 or 240 mg/kg) of berberine in rats. For excretion study, rats were intragastrically administered a single dose of 48.2 mg/kg berberine. Our results showed that berberine could be metabolized rapidly and all the nine metabolites could be detected in vivo. The absolute bioavailability of berberine was 0.37 ± 0.11%. As for the AUC0–48 h values, phase II metabolites were much higher than those of phase I metabolites, suggesting that phase II metabolites were the major metabolites exist in blood circulation. 18.6% of the berberine was excreted in feces as berberrubine (M1). The total recovery of berberine and its nine metabolites from urine, bile and feces was 41.2%. This is the first systematic study about the pharmacokinetics and excretion of berberine and its nine metabolites, which will be beneficial for both better understanding the clinical effects and further development of berberine.
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