Pharmacokinetics of five phthalides in volatile oil of Ligusticum sinense Oliv.cv. Chaxiong, and comparison study on physicochemistry and pharmacokinetics after being formulated into solid dispersion and inclusion compound

Peng-Yi Hu,Guo-Song Zhang,Dong-Xun Li,Ying-Huai Zhong,Xue-Mei Liu,Ping Deng,Jian-Fang Feng,Wen-Liu Zhang,Zhi-Qiang Lei

doi:10.1186/s12906-021-03289-z

Abstract

BackgroundsThe dried rhizome of Ligusticum sinense Oliv.cv. Chaxiong has been used to treat cardiovascular and cerebrovascular diseases, atherosclerosis, anemia and stroke. A high purity extract from chaxiong (VOC, brownish yellow oil) was extracted and separated. Its main components were senkyunolide A (SA, 33.81%), N-butylphthalide (NBP, 1.38%), Neocnidilide (NOL, 16.53%), Z-ligustilide (ZL, 38.36%), and butenyl phthalide (BP, 2.48%), respectively. Little is known about the pharmacokinetics of these phthalides in Chaxiong, and different preparations to improve the physicochemistry and pharmacokinetics of VOC have not been investigated.MethodsAt different predetermined time points after oral administration or intravenous administration, the concentrations of SA, NBP, NOL, ZL and BP in the rat plasma were determined using LC-MS/MS, and the main PK parameters were investigated. VOC-P188 solid dispersion and VOC-β-CD inclusion compound were prepared by melting solvent method and grinding method, respectively. Moreover, the physicochemical properties, dissolution and pharmacokinetics of VOC-P188 solid dispersion and VOC-β-CD inclusion compound in rats were assessed in comparison to VOC.ResultsThe absorptions of SA, NBP, NOL, ZL and BP in VOC were rapid after oral administration, and the absolute bioavailability was less than 25%. After the two preparations were prepared, dissolution rate was improved at pH 5.8 phosphate buffer solution. Comparing VOC and physical mixture with the solid dispersion and inclusion compound, it was observed differences occurred in the chemical composition, thermal stability, and morphology. Both VOC-P188 solid dispersion and VOC-β-CD inclusion compound had a significantly higher AUC and longer MRT in comparison with VOC.ConclusionSA, NBP, NOL, ZL and BP in VOC from chaxiong possessed poor absolute oral bioavailability. Both VOC-P188 solid dispersion and VOC-β-CD inclusion compound could be prospective means for improving oral bioavailability of SA, NBP, NOL, ZL and BP in VOC.

Highlights

Stroke, a common neurological disease with a high risk of suddenness, disability or death, is mainly caused by atherosclerosis, vasospasm, cerebral ischemia and hypoxia
The absorptions of Senkyunolide A (SA), NBP, NOL, ZL and Butenyl phthalide (BP) in Volatile oil of chaxiong (VOC) were rapid after oral administration, and the absolute bioavailability was less than 25%
Comparing VOC and physical mixture with the solid dispersion and inclusion compound, it was observed differences occurred in the chemical composition, thermal stability, and morphology

Summary

Introduction

A common neurological disease with a high risk of suddenness, disability or death, is mainly caused by atherosclerosis, vasospasm, cerebral ischemia and hypoxia. It is the second largest cause of death in the world [26, 27]. It impairs capabilities of communication, cognition, and motor function in patients, so it substantially affects the quality of life of stroke patients [2]. Some monomeric phthalides have shown their ability to attenuate certain neurological diseases, including stroke, Alzheimer’s and Parkinson’s diseases [15]. Some new phthalides and some known phthalides in chaxiong were extracted and separated, and had been shown to have a protective effects against neuronal impairment induced by deprival of oxygen and glucose [35, 36]

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