1. The exposure of highly toxic aconitine does not significantly impact the activity and expression of cytochrome P450 3A in rats determined by a novel ultra performance liquid chromatography-tandem mass spectrometric method of a specific probe buspirone.
- Author
-
Zhu L, Yang X, Zhou J, Tang L, Xia B, Hu M, Zhou F, and Liu Z
- Subjects
- Aconitine administration & dosage, Aconitum chemistry, Administration, Oral, Animals, Buspirone analogs & derivatives, Buspirone analysis, Buspirone metabolism, Liver drug effects, Liver metabolism, Male, Medicine, Chinese Traditional, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Rats, Rats, Sprague-Dawley, Reproducibility of Results, Aconitine toxicity, Buspirone pharmacokinetics, Chromatography, Liquid methods, Cytochrome P-450 CYP3A metabolism, Drug Interactions, Tandem Mass Spectrometry methods
- Abstract
Aconitum species are widely used to treat rheumatism, cardiovascular diseases, and tumors in China and other Asian countries. The herbs are always used with drugs such as paclitaxel. Aconitine (AC) is one of the main bioactive/high-toxic alkaloids of Aconitum roots. AC is metabolized by cytochrome P450 (CYP) 3A. However, whether AC inhibits/induces CYP3A, which causes drug-drug interaction (DDI) is unclear. Our study aims to explore the potent effects of AC, as a marker component of Aconitum, on CYP3A using the probe buspirone in rats. The effects of oral AC on pharmacokinetics of buspirone were evaluated. CYP3A activity and protein levels in rat liver microsomes pretreated with oral AC were also measured using in vitro buspirone metabolism and Western blot. Buspirone and its major metabolites 1-(2-pyrimidinyl)piperazine and 6'-hydroxybuspirone were determined using a newly validated UPLC-MS/MS method. Single dose and 7-day AC administration at 0.125mg/kg had no effect on CYP3A activity since no change in the formation of 1-(2-pyrimidinyl)piperazine and 6'-hydroxybuspirone. CYP3A activity and protein levels in liver microsomes were also not affected by 7-day AC pretreatment at 0.125mg/kg. Therefore, AC neither inhibits nor induces CYP3A in rats, indicating AC does not cause CYP3A-related DDI in the liver., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF