| The compatibility between Radix Aconiti Lateralis and Radix Glycyrrhizae, a classic traditional Chinese medicine pair, belong to mutual restraint and mutual detoxication. Although there have been lots of studies on it, the mechanism of its combination effect that toxicity reduction and pharmacologic effect improvement has not been revealed.Objective:In this article, we aim to explain the compatibility mechanism based on our hypothesis, which we put forward for the first time, that the combination effect would be realized by means of the behavior changes both in vivo and in vitro.Method and Result:The whole research content is composed of three parts. In the first part, we investigate the optimal boiling time as30minutes by the content dynamic changes of total alkaloids and diester-alkaloids. Meantime, we also evaluate the toxicity of decoction stemmed from this condition. In the second part, we have estimated the simultaneous determination method of six ester alkaloids in supernatant of single Radix Aconiti Lateralis decoction and Radix Aconiti Lateralis-Radix Glycyrrhizae decoction We have estimated the common fingerprint pattern of fourteen batches of single Radix Aconiti Lateralis decoction and Radix Aconiti Lateralis-Radix Glycyrrhizae decoction respectively, in which we have identified twenty and thirty two kind of compounds name and structure. The pharmacokinetics of hypaconitine in between single Radix Aconiti Lateralis decoction and Radix Aconiti Lateralis-Radix Glycyrrhizae decoction in rats were contracted, of which results showed the absorption rate of hypaconitine was slowed but the total absorption area of hypaconitine was added after the compatibility of Radix Glycyrrhizae. In the last part, focusing on the sediments stemmed on the bottom of decoction, we have identified twenty eight and thirty two kind of compounds in sediments of single Radix Aconiti Lateralis decoction and Radix Aconiti Lateralis-Radix Glycyrrhizae decoction respectively. We also investigated the intestinal absorption characteristics of aconitine, hypaconitine and mesaconine using everted gut sacs and in situ perfusion model, in which the result could be gotten that diester-alkaloids in sediments could be significantly absorbed in ileum (P<0.05) and these compounds could be the substrates of P-gp and fit the passive absorption. In addition, we determinate the pharmacokinetic parameters of aconitine, hypaconitine and mesaconine in sediments of Radix Aconiti Lateralis-Radix Glycyrrhizae decoction, whose results showed they have good oral bioavailability.Conclusion:In this article, we have successfully confirmed our hypothetical idea that the main toxic and effective constituent in Radix Aconiti Lateralis would be composited and deposited in decoction firstly, as well as liberated and absorbed slowly in small intestine after boiling Radix Aconiti Lateralis with Radix Glycyrrhizae together. Though our experiments, we have uncovered the compatibility theory mechanism about how to reduce Radix Aconiti Lateralis toxicity but not pharmacological effect after combination of Radix Glycyrrhizae. The article would put forward a new thinking for research the traditional Chinese medicine compatibility theory and the mechanism of drugs interaction.Innovative points:There would be two innovative points in this article. The first one would be that using HPLC-Q-TOF/MS we have identified the constituent in both decoction and sediments of single Radix Aconiti Lateralis decoction and Radix Aconiti Lateralis-Radix Glycyrrhizae decoction respectively for the first time. This method could avoid the complicated component separation link. The second one would be that using intestinal absorption models we have revealed the rationality of our idea about compounds in sediments released again in vivo by evaluating the intestinal absorption characteristics of aconitine, hypaconitine and mesaconitine. |
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