Pharmacokinetics and metabolism of jatrorrhizine, a gastric prokinetic drug candidate

Abstract

Jatrorrhizine, a protoberberine alkaloid derived from Coptis chinensis, is currently under investigation as a natural gastric prokinetic drug candidate. In vitro and in vivo studies were conducted to characterize its pharmacokinetics and metabolism. After intravenous administration, the plasma concentration kinetics and major metabolites in rats were investigated. The metabolic kinetics, key cytochrome P450 enzymes and UDP-glucuronosyltransferase isoforms (UGTs) of jatrorrhizine were studied in rat liver microsomes (RLMs). After intravenous administration, plasma jatrorrhizine concentrations showed a biphasic decline, dose-independent clearance and half-life of terminal elimination phase, and a relatively large distribution volume. The metabolic pathway for the conversion of jatrorrhizine was important for its elimination. In addition, the demethylated and glucuronidated products were found to be the major metabolites in rats. The enzyme kinetics for both demethylation and glucuronidation were fitted to the hyperbolic Michaelis-Menten equation in RLMs. CYP3A1/2 and CYP2D2 were mainly responsible for demethylation, and UGT 1A1 and 1A3 were responsible for glucuronidation in RLMs. The metabolic properties of jatrorrhizine suggest multiple metabolic pathways. These results will contribute to promote further research and development of jatrorrhizine.

Simultaneous determination of eight bioactive components in rat plasma after oral administration of Yan‐Ke‐Ning‐Tablet by liquid chromatography coupled with Q‐Exactive Orbitrap tandem mass spectrometry

“…In contrast, baicalin, baicalein and wogonin showed higher plasma exposure with AUC 0– t values being 1201.50 ± 239.09, 957.63 ± 187.08, and 662.38 ± 221.02 ng h/mL, respectively. The mean half‐lives were 4.31, 5.34, 5.77, 6.89, 6.25, 4.78, 5.76, and 5.31 h for berberine, berberrubine, palmatine, jatrorrhizine, columbamine, baicalin, baicalein and wogonin, respectively, which were comparable with those reported in the literature (Deng et al, ; Shi et al, ; Wang, Yao, An, You, & Wang, ).…”

Metabolism of the Hepatotoxic Compound Sophoraflavanone G in Rat Liver Microsomes

“…Chemical inhibition is a common and simple method for screening CYP isoforms of RLMs (Ruan and others ; Shi and others ), but chemical inhibition combined with other methods including recombinant CYPs, antibody neutralization, and correlation analysis is required in order to obtain accurate results (Yan and Caldwell ) because most chemical inhibitors inhibit more than one CYP isoforms. However, according to previously published reports, furafylline being a selective inhibitor for rat CYP1A2 (Eagling and others ; Kobayashi and others ) and diethyldithiocarbamate being a selective inhibitor for rat CYP2E1 (Liu and others ; Shi and others ), it can initially be considered that CYP1A2 and CYP2E1 played predominant roles in the mono‐hydroxylation of SFG. Thus, the combination of SFG with CYP1A2 inhibitors such as fluvoxamine or CYP2E1 inhibitors such as clomethiazole (Tucker and others ) may increase the hepatotoxicity of SFG.…”

“…Because no valid UGT inhibitors of rat liver activity were used, the exact UGT isoforms responsible for the formation of M4 and M5 cannot be determined. However, according to previously published reports, 1‐naphthol (for rat UGT 1A6/1A8), β‐estradiol (for rat UGT1A1), and phenylbutazone (for human UGT1A) were also used as inhibitors in RLMs (Di Marco and others ; Tian and others ; Liu and others ; Shi and others ), it can initially be considered that multiple UGT1A isoforms catalyzed the formation of M4 and M5 in RLMs. The results also suggested that interactions at the level of metabolism may also take place when SFG was combined with drugs that can inhibit or induce UGT1A.…”

“…The inhibitory effects of selective CYP enzyme inhibitors on the formation of M2 were evaluated in RLMs. Well‐characterized specific CYP inhibitors used were: 1 and 10 μM furafylline (for rat CYP1A2; Eagling and others ; Kobayashi and others ), 1 and 10 μM quinidine (for rat CYP2D2, CYP2C6, and CYP2C11; Bogaards and others ; Choi and Lee ), 1 and 10 μM ketoconazole (for rat CYP1A2, CYP2C6, and CYP3A1/2; Mandlekar and others ), 10 and 100 μM diethyldithiocarbamate (for rat CYP2E1; Liu and others ; Shi and others ), 10 and 100 μM sulfaphenazole (for rat CYP2C6/C11; Chung and others ). The inhibitors were co‐incubated with 40 or 400 μM SFG in RLMs.…”

“…Several well‐characterized UGT substrates were used as inhibitors to screen the involvement of UGTs in the formation of M4 and M5. These inhibitors were used as following: 10 to 100 μM β‐estradiol (for rat UGT1A1; Tian and others ; Liu and others ), 10 to 200 μM 1‐naphthol (for rat UGT1A6 and 1A8; Di Marco and others ), 20 to 400 μM propofol (for human UGT1A9; Radominska‐Pandya and others ; Liu and others ), 100 to 1000 μM phenylbutazone (for human UGT1A; Shi and others ), 25 to 500 μM fluconazol (for human UGT2B7; Uchaipichat and others ; Mano and others ). The inhibitors were co‐incubated with 60 μM SFG in RLMs.…”