Pharmacokinetics and pharmacodynamics analysis of XQ-1H and its combination therapy with clopidogrel on cerebral ischemic reperfusion injury in rats.

Abstract

Ischemic stroke is the main cause of disability and mortality worldwide. 10-O-(N N-dimethylaminoethyl)-ginkgolide B methane-sulfonate (XQ-1 H) is a novel drug based on the remedial approach for ischemic stroke. Clopidogrel, a widely used anti-platelet drug, is often co-prescribed in the clinic. In this study, we established an UPLC-MS/MS spectrometry method for the determination of XQ-1H and investigated the pharmacokinetic effect of clopidogrel on XQ-1H in rats subjected to middle cerebral artery occlusion (MCAO). Meanwhile, the anti-apoptotic and neuroprotective effects of XQ-1H and its combination with clopidogrel were also studied. The results revealed that XQ-1H and its combination with clopidogrel abridged brain infarct volume, cerebral edema and alleviated neurological dysfunction caused by cerebral ischemic reperfusion injury. Further study demonstrated that XQ-1H combined with clopidogrel lessened TUNEL positive cells, up-regulated bcl-2 expression notably and down-regulated bax expression as compared to both XQ-1H and clopidogrel individually. In addition, a rapid, sensitive UPLC-MS/MS method was developed to quantify the concentration of XQ-1H in MCAO/R rats. Our pharmacokinetic results showed that clopidogrel significantly increased the exposure of XQ-1H, increased the peak plasma concentration (Cmax), area under the curve (AUC) and slowed elimination of XQ-1H in the co-administered group. Besides, for further exploring which CYP450 isoforms are involved in the XQ-1H metabolism, XQ-1H was incubated in human liver microsomes (HLMs) system with or without P450 isoform-selective inhibitors. Our results revealed that clopidogrel altered pharmacokinetics of XQ-1H potentially and subsequently enhanced the pharmacological effect of XQ-1H. Moreover, XQ-1H could be applied as an efficacious neuroprotective agent for ischemic stroke because of its considerable effect on averting neuronal apoptosis.

• Authors: Bayarmaa Khadankhuu, Yuxiang Fei, Dan Xu, Yingchao Li, Kai Hou, Fengyang Li, Weirong Fang, Xijing Chen, Yunman Li
• Journal: Journal of pharmaceutical and biomedical analysis (J Pharm Biomed Anal) Vol. 179 Pg. 112975 (Feb 05 2020) ISSN: 1873-264X [Electronic] England
• PMID: 31735472 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Bax protein, rat
• Ginkgolides
• Lactones
• Proto-Oncogene Proteins c-bcl-2
• XQ-1H compound
• bcl-2-Associated X Protein
• Clopidogrel

Topics

• Animals
• Apoptosis (drug effects)
• Brain (metabolism, pathology)
• Brain Ischemia (blood, complications)
• Chromatography, High Pressure Liquid (methods)
• Clopidogrel (pharmacology)
• Drug Synergism
• Ginkgolides (blood, chemistry, pharmacokinetics, pharmacology)
• Humans
• Infarction, Middle Cerebral Artery
• Lactones (blood, chemistry, pharmacokinetics, pharmacology)
• Male
• Microsomes, Liver (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis)
• Rats
• Reperfusion Injury (blood, prevention & control)
• Tandem Mass Spectrometry (methods)
• bcl-2-Associated X Protein (biosynthesis)