Investigation of the influence of glycyrrhizin on the pharmacokinetics of celastrol in rats using LC-MS and its potential mechanism

Abstract

1. The aim of this study was to investigate the effects of glycyrrhizin on the pharmacokinetics of celastrol in rats. 2. Twelve male Sprague-Dawley rats were randomly assigned to two groups: control group and test group. Test group was pretreated with glycyrrhizin at a dose of 100 mg/kg/day for 10 days, and then the two groups were orally administered with celastrol at a dose of 1 mg/kg. The concentration of celastrol was determined using a sensitive and reliable LC-MS method. 3. The results showed that glycyrrhizin could significantly decrease the plasma concentration (from 64.36 ng/mL to 38.42 ng/mL) and AUC (from 705.39 to 403.43 μg·h/L) of celastrol in rats. To investigate its potential mechanism, the effects of glycyrrhizin on the transport and metabolic stability of celastrol were investigated using Caco-2 cell monolayer transwell model and rat liver microsome incubation systems. The Caco-2 cell monolayer transwell experiments indicated that glycyrrhizin could increase the efflux ratio of celastrol (4.02 versus 6.51). However, the rat liver microsome incubation experiments showed that glycyrrhizin could significantly increase the intrinsic clearance rate of celastrol from 20.3 ± 3.37 to 38.8 ± 4.18 μL/min/mg protein. 4. In conclusion, these results indicated that the herb-drug interaction between glycyrrhizin and celastrol might occur when they were coadministered.

Celastrol attenuates impairments associated with lipopolysaccharide-induced acute respiratory distress syndrome (ARDS) in rats

“…A key limitation of this study is that no data regarding pharmacokinetics or metabolism of celastrol were derived. Previous studies suggested the half-life of celastrol is around 8 h (Yan et al 2017), and complexation, enterohepatic recirculation, gastric secretion-enteral reabsorption or others may affect localized levels of celastrol at any given time (Zhang et al 2012). Although it is certain celastrol could protect against LPS-induced lung injury and inflammation, it is unclear whether the agent might be retained (or accumulate) in the lung.…”

Effects of glycyrrhizin on the pharmacokinetics of nobiletin in rats and its potential mechanism

“…GL decreased the system exposure of asiatic acid by inducing the activity of CYP450 enzymes (Guo et al 2018), and GL increased the clearance rate of paeoniflorin via inducing the activity of CYP3A4 (Sun et al 2019). The co-administration of GL and celastrol could decrease the plasma concentration of celastrol, due to the enhancement GL exerted on the activity of CYP3A4 (Yan et al 2017).…”

“…Rat liver microsomes were used to investigate the effects of GL on the metabolism clearance of NBL, and the assay conditions and reaction mixtures were similar to those reported previously (Wang et al 2017;Yan et al 2017). In brief, 30 lL rat liver microsome (20 mg/mL), 12 lL NBL solution (100 lM) and 1113 lL PBS buffer (0.1 M, pH 7.4) were added to the centrifuge tubes on ice.…”

“…It has been reported that GL can modulate the activity of CYP3A4 and P-gp, which might lead to drug-drug interaction (Tu et al 2010;. Co-administration of different drugs is common in traditional Chinese medicine, and GL has been reported to inhibit the effect of other drugs (Chen et al 2017;Yan et al 2017;.…”

Effects of glycyrrhizin on the pharmacokinetics of asiatic acid in rats and its potential mechanism

“…Yan et al. ( 2017 ) have also indicated that glycyrrhizin could decrease the systemic exposure of celastrol when they are co-administered. Previous studies have also reported that the mechanism of licorice to reconcile various drugs may be related to induction of CYP3A4 or P-gp expression, thereby accelerating the metabolism or efflux of co-administered TCM or toxic constituents in other TCMs and decreasing the toxicity thereafter (Chen et al.…”