Qing-Shan Zhang1, Gao-Wa Wang1, Zhi-Qiang Han2, Xiang-Mei Chen3, Risu Na1, Haburi Jin1, Ping Li1, Renbatu Bu1. 1. Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, 028000, P.R. China. 2. Medical Institution Conducting Clinical Trials for Human Used Drug of Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, 028000, PR China. 3. Mongolian Medicine College of Pharmacy of Inner Mongolia University for the Nationalities, Tongliao, 028000, PR China.
Abstract
RATIONALE: Rhizoma coptidis extract and its alkaloids show various pharmacological activities, but its metabolic profile in human plasma has not been thoroughly investigated. In the present research, the metabolism of Rhizoma coptidis at a clinical dose (5 g/60 kg/day) was systematically analyzed to determine its biotransformation processes in human plasma. METHODS: In this research, the metabolites of Rhizoma coptidis in human plasma after oral administration of Rhizoma coptidis extract at a clinical dose were investigated using ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution LTQ-Orbitrap mass spectrometry. The structural elucidation of the constituents was confirmed by comparing their retention times (tR ) and MSn fragments with those of standards and literature reports. RESULTS: In total, two prototypes and twelve metabolites were detected in human plasma. The two prototypes were confidently identified using reference standards. Of the compounds detected, M7 (berberrubinen-9-O-glucuronide) was the most abundant based on its peak area, which indicates that this compound might be a pharmacokinetic marker for Rhizoma coptidis alkaloids in humans. Based on the metabolites detected in human plasma, a possible metabolic pathway for Rhizoma coptidis in vivo was proposed. CONCLUSIONS: The results indicated that the alkaloids in Rhizoma coptidis were extensively biotransformed in vivo mainly via conjugation with glucuronic acid (GluA) or sulfuric acid (SulA) to form phase II metabolites, and the GluA metabolites are likely the dominant form in human plasma. To the best of our knowledge, this is the first in vivo evaluation of the metabolic profile of the whole Rhizoma coptidis extract in human plasma, which is essential for determining the chemicals responsible for the pharmacological activities of Rhizoma coptidis in vivo. Moreover, it would be beneficial for us to further systematically study the pharmacokinetic behavior of Rhizoma coptidis in humans.
RATIONALE: Rhizoma coptidis extract and its alkaloids show various pharmacological activities, but its metabolic profile in human plasma has not been thoroughly investigated. In the present research, the metabolism of Rhizoma coptidis at a clinical dose (5 g/60 kg/day) was systematically analyzed to determine its biotransformation processes in human plasma. METHODS: In this research, the metabolites of Rhizoma coptidis in human plasma after oral administration of Rhizoma coptidis extract at a clinical dose were investigated using ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution LTQ-Orbitrap mass spectrometry. The structural elucidation of the constituents was confirmed by comparing their retention times (tR ) and MSn fragments with those of standards and literature reports. RESULTS: In total, two prototypes and twelve metabolites were detected in human plasma. The two prototypes were confidently identified using reference standards. Of the compounds detected, M7 (berberrubinen-9-O-glucuronide) was the most abundant based on its peak area, which indicates that this compound might be a pharmacokinetic marker for Rhizoma coptidis alkaloids in humans. Based on the metabolites detected in human plasma, a possible metabolic pathway for Rhizoma coptidis in vivo was proposed. CONCLUSIONS: The results indicated that the alkaloids in Rhizoma coptidis were extensively biotransformed in vivo mainly via conjugation with glucuronic acid (GluA) or sulfuric acid (SulA) to form phase II metabolites, and the GluA metabolites are likely the dominant form in human plasma. To the best of our knowledge, this is the first in vivo evaluation of the metabolic profile of the whole Rhizoma coptidis extract in human plasma, which is essential for determining the chemicals responsible for the pharmacological activities of Rhizoma coptidis in vivo. Moreover, it would be beneficial for us to further systematically study the pharmacokinetic behavior of Rhizoma coptidis in humans.