Metabolic profile of Rhizoma coptidis in human plasma determined using ultra‐high‐performance liquid chromatography coupled with high‐resolution mass spectrometry

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 ultrahigh-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 (t R ) and MS n 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.

Metabolic profile of alkaloids in Rhizoma Coptidis in rat plasma, urine and feces after oral administration using ultra‐high‐performance liquid chromatography coupled with quadrupole time‐of‐flight mass spectrometry

“…In MS/MS spectra, a product ion [M − glcUA] + was detected at m/z 342.1328, which had one H 2 O more and one C less than berberine, suggesting that M43 might be a derivative of berberine arising from hydroxylation, demethylenation and reduction. By comparison with the literature, M43 was tentatively assigned as a hydroxylated dihydrademethyleneberberine‐ O ‐glucuronide conjugate.…”

“…In MS/MS spectra, the [M] + ion yielded product ions at m/z 338.1378 [M − SO 3 ] + , 322.1136 [M − SO 3 − CH 4 ] + and 294.1097 [M − SO 3 − CH 4 − CO] + . By comparison with the literature, M64 was assigned as jatrorrhizine‐3‐ O ‐sulfate.…”

“…In MS/MS spectra, the [M] + ion showed product ions at m/z 322.1066 [M − glcUA] + and 307.0834 [M − glcUA − CH 3 ] + , suggesting that M30 , M31 and M32 might be glucuronide conjugates. Thus, M31 was speculated to be either tetradehydroscoulerine‐ O ‐glucuronide or groenlandicine‐ O ‐glucuronide by comparison with the literature and by its retention time, while M30 and M32 were assigned as berberrubine‐ O ‐glucuronide and thalifendine‐ O ‐glucuronide, respectively …”

“…Thus, the study of metabolites is valuable to elucidate the material basis of TCM. The therapeutic effect of RC is the superimposed effect of the prototype components and metabolites . However, there is little information available on the in vivo chemical components of RC following oral administration.…”

Systematic screening and characterization of absorbed constituents and in vivo metabolites in rats after oral administration of Rhizoma coptidis using UPLC‐Q‐TOF/MS

“…However, pharmacokinetic studies showed that the plasma concentrations of protoberberine‐type alkaloids were so low that the systemic therapeutic actions of Rhizoma coptidis could not be explained, promoting the hypothesis that the in vivo metabolites may also exert biological activities (Sun et al, 2017; Zi‐Min et al, 2017). Although several investigations focusing on the metabolism of orally administered Rhizoma coptidis extract have been reported (Li et al, 2015, 2017; Q. Zhang, Wang, Chen, et al, 2018; Q. S. Zhang, Wang, Han, et al, 2018), the metabolic profiles of Rhizoma coptidis in vivo are not yet fully understood.…”