Pharmacokinetics Studies of 12 Alkaloids in Rat Plasma after Oral Administration of Zuojin and Fan-Zuojin Formulas

Abstract

Zuojin formula (ZJ) is a traditional Chinese medicine (TCM) prescription consisted of Coptidis Rhizoma (CR) and Euodiae Fructus (EF), and has been used to treat gastrointestinal (GI) disease for more than 700 years. Fan-Zuojin formula (FZJ) is a related TCM prescription also consisted of CR and EF with the opposite proportion. In recent years, ZJ was getting more attention for its antitumor potential, but the indeterminate pharmacokinetic (PK) behavior restricted its clinical applications, and the PK differences between ZJ and FZJ were also largely unknown. Consequently it is necessary to carry out a full-scale PK study to demonstrate the physiological disposition of ZJ, as well as the comparative PK study between ZJ and FZJ to illustrate the compatibility dose effects. Therefore a liquid chromatographic–tandem mass spectrometry (LC–MS/MS) method was established and validated for the determinations of coptisine, epiberberine, palmatine, berberine, 8-oxocoptisine, 8-oxoepiberberine, noroxyhydrastinine, corydaldine, dehydroevodiamine, evodiamine, wuchuyuamide-I, and evocarpine in rat plasma. PK characteristics of 12 alkaloids after oral administration of ZJ and FZJ were compared, and the result was analyzed and discussed with the help of an in silico study. Then an integrated PK study was carried out with the AUC-based weighting method and the total drug concentration method. The established method has been successfully applied to reveal the PK profiles of the 12 alkaloids in rat plasma after oral administration of ZJ and FZJ. The results showed that: (1) double peaks were observed in the plasma concentration-time (C–T) curves of the alkaloids after ZJ administration; but the C–T curves approximately matched the two-compartment model after FZJ administration; (2) There were wide variations in the absorption levels of these alkaloids; and even for a certain alkaloid, the dose modified systemic exposure levels and elimination rate also varied significantly after administration of ZJ and FZJ extracts. The results could be interpreted as follows: firstly, inhibition effect on GI motility caused by the high content CR alkaloids (especially berberine) in ZJ could delay the Tmax, and increase the absorption and systemic exposure levels of the other alkaloids, and also lead to the double peak phenomenon of these alkaloids. However, for quaternary protoberberine alkaloids (QPA), double peaks were primarily caused by the different Ka value in two intestinal absorption sites; Secondly, absorption was the major obstacle to the systemic exposure level of the alkaloids from CR and EF. In silico and PK studies suggested that the absorption of these alkaloids, except QPAs, mainly depended on their solubility rather than permeability; Thirdly, EF could promote the absorption and accelerate the elimination of QPAs, and had a greater influence on the former than the latter. At last the integrated PK analysis suggested that berberine and dehydroevodiamine could be regarded as the representative components to reflect the PK behaviors o...

Simultaneous determination of baicalin, baicalein, wogonoside, wogonin, scutellarin, berberine, coptisine, ginsenoside Rb1 and ginsenoside Re of Banxia xiexin decoction in rat plasma by LC–MS/MS and its application to a pharmacokinetic study

“…In the current study, multiple absorption peaks were observed in plasma concentration–time curves of berberine and coptisine after oral administration of BXD to rats, which were once thought to be due to enterohepatic circulation and tissue distribution accompanied by blood re‐absorption in rats. However, research findings are suggesting that the site‐specific absorption instead of enterohepatic circulation could be the major reason for the multi‐peak phenomenon of berberine and coptisine (Li, Lin, et al, ; Li, Ren, et al, ; Li, Zhang, et al, ; Qian, Zhang, Yang, Xu, & Yang, ; Tan, Guo, & Zhong, ). Comparing dose‐modified C max and AUC (0 –t ) values (Table ) of berberine and coptisine with the previous pharmacokinetic studies (Feng et al, ; Qian et al, ), it was repeatedly found that the absorption of the alkaloids was greatly improved in herbal prescriptions.…”

Coptidis rhizoma and its main bioactive components: recent advances in chemical investigation, quality evaluation and pharmacological activity

“…The traditional Chinese anti-diabetic formula, Jinqi formula (Coptidis rhizoma, Astragali rhadix and Lonicerae japonicae Flos) could inhibit TG accumulation [ 85 ]. Zuojin and Fan-Zuojin formulas with reverse mixture ratios of CR and Euodiae fructus led to different interactions on the in vitro absorption of alkaloids and opposite effects [ 86 , 87 ]. Ge-Gen-Qin-Lian-Tang could decrease lipid formation [ 88 ].…”

The compatibility of six alkaloids in ermiao pill explored by a comparative pharmacokinetic and network pharmacological study

“…Other structural analogs were reported in a previous study (Sun et al, ). This might be due to the inhibition of berberine on gastrointestinal motility (Qian, Zhang, Yang, Xu, & Yang, ).…”