Simultaneous determination of evodiamine and its four metabolites in rat plasma by LC–MS/MS and its application to a pharmacokinetic study

Abstract

A simple and sensitive liquid chromatography tandem mass spectrometry method was validated for simultaneous quantification of evodiamine and its metabolites 10-hydroxyevodiamine (M1), 18-hydroxyevodiamine (M2), 10-hydroxyevodiamine-glucuronide (M3) and 18-hydroxy- evodiamine-glucuronide (M4) in rat plasma for the first time. The analytes were extracted with acetonitrile and separated on a C column within 3 min. The detection was achieved in positive selected reaction monitoring mode with precursor-to-product transitions at m/z 304.1 → 161.1 for evodiamine, m/z 320.1 → 134.1 for M1, m/z 320.1 → 150.1 for M2, m/z 496.2 → 134.1 for M3, m/z 496.2 → 171.1 for M4 and m/z 349.2 → 305.1 for camptothecin (internal standard). The linearity was evident over the tested concentration ranges with correlation coefficients >0.9991. The lower limits of quantification for evodiamine, M1, M2, M3 and M4 were 0.1, 0.1, 0.1, 0.25 and 0.25 ng mL , respectively. Extraction recoveries and matrix effects of the analytes were within the ranges of 84.51-97.21 and 90.13-103.30%, respectively. The accuracy (relative error) ranged from -8.14 to 7.23% while the intra- and inter-day precisions (relative standard deviation) were < 9.31%. The validated assay was successfully applied for the pharmacokinetic study of evodiamine, M1, M2, M3 and M4 in rat. The current study will be helpful in understanding the in vivo disposition of evodiamine.

Research progress on evodiamine, a bioactive alkaloid of Evodiae fructus: Focus on its anti‑cancer activity and bioavailability (Review)

“…The radioactivity levels in the plasma reached their maximum level within 1 h of oral administration, which declined in a biphasic manner, with half-times of 1.6 and 78.4 h (84). EVO has also been reported to reach a maximum plasma concentration in rat 3.38 h (T max ) after oral administration (35). EVO is predominantly distributed in the liver, kidney, heart and lungs, where 19 and 63% of orally administered EVO is eliminated in the urine and bile after 24 h, respectively (84).…”

“…A previous study demonstrated that EVO is readily susceptible to metabolism, forming hydroxylation metabolites, which exhibit potent cytotoxicity compared with that mediated by EVO (35). Furthermore, another study suggested that the 3-alkylindole moiety on EVO is a potential toxicophore in P450-mediated dehydrogenation reactions (34).…”

“…Drug metabolism serves crucial roles in the bioavailability and subsequent pharmacological activities of poorly soluble, naturally occurring therapeutic agents, which significant impacts their toxicity profile and side effects (33). Previous studies have reported that the toxicity of EVO may be associated with its mechanism of metabolism in vivo and pharmacokinetics (34,35). EVO is readily susceptible to metabolism, P450 enzymes-mediated dehydrogenation reactions may cause toxicity via formation of electrophilic intermediates, then produce glutathione (GSH)-conjugated metabolites to exert more potent cytotoxic effects than EVO itself (34).…”

Pharmacokinetics of B-Ring Unsubstituted Flavones

“…In the case of GL-V9, although a concentration peak was seen after 0.5 h of oral administration, a second twin peak was recorded after 12 h (in rats), most likely related to the enterohepatic, enteric, or local recycling [60]. A double peak was detected in the plasma concentration–time curves for baicalin, oroxin A (baicalein-7- O -glucoside), baicalein, wogonoside, wogonin, and chrysin when administered in rats, related to enterohepatic, local, or enteric recycling [16,23,32,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100]. In one study in rats, it was claimed that this bi-modal “behavior” was not confirmed experimentally [101], but the authors only measured plasma samples up to 180 min, whereas in order to observe the second peak (at its maximum) at least 6–8 h would often be needed [102,103,104,105], although in other cases a second peak was reported after only two to three hours [106,107,108,109]; in dogs, following i.v.…”

A validated LC–MS/MS method for the determination of RAF inhibitor LXH254: Application to pharmacokinetic study in rat

“…Therefore, to support the pharmacokinetic study, development and validation of a simple and sensitive assay is necessary. Due to the high sensitivity and selectivity, UHPLC–MS/MS has received considerable attention, and now it is the most commonly preferred technique for biomedical analysis (Han, Yang, Ding, Ji, & Zhang, 2015; Iqbal, Ezzeldin, Khalil, Alam, & Al‐Rashood, 2018; Wang, Yue, Ai, & Yang, 2018; Yi & Lan, 2020; Zhao, Wu, Liu, Zhang, & Lin, 2014).…”