Pharmacokinetics and Brain Distribution and Metabolite Identification of Coptisine, a Protoberberine Alkaloid with Therapeutic Potential for CNS Disorders, in Rats

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  • Su Jin
    School of Chinese Materia Medica, Beijing University of Chinese Medicine School of Pharmacy, Jiamusi University
  • Miao Qing
    School of Chinese Materia Medica, Beijing University of Chinese Medicine
  • Miao Peipei
    School of Chinese Materia Medica, Beijing University of Chinese Medicine
  • Zhao Yuanyuan
    School of Chinese Materia Medica, Beijing University of Chinese Medicine
  • Zhang Yuanyuan
    School of Chinese Materia Medica, Beijing University of Chinese Medicine
  • Chen Ning
    School of Chinese Materia Medica, Beijing University of Chinese Medicine
  • Zhang Yujie
    School of Chinese Materia Medica, Beijing University of Chinese Medicine
  • Ma Shuangcheng
    National Institutes for Food and Drug Control

書誌事項

公開日
2015
資源種別
journal article
DOI
  • 10.1248/bpb.b15-00293
公開者
公益社団法人 日本薬学会

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説明

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 (Kp, 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 (T1/2=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.

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