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

Bayarmaa Khadankhuu,Yuxiang Fei,Dan Xu,Yingchao Li,Kai Hou,Fengyang Li,Weirong Fang,Xijing Chen,Yunman Li

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 (C max ), 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.