%0 Journal Article
%T Role of P-glycoprotein in Regulating the Efficacy, Toxicity and Pharmacokinetics of Yunaconitine.
%A Li X
%A Liang Q
%A Wang C
%A Qiu H
%A Lin T
%A Li W
%A Zhang R
%A Liu Z
%A Zhu L
%J Curr Drug Metab
%V 0
%N 0
%D 2024 Aug 6
%M 39108114
%F 3.408
%R 10.2174/0113892002302427240801072910
%X <B>BACKGROUND: </B>Yunaconitine (YAC) is a hidden toxin that greatly threatens the life safety of patients who are prescribed herbal medicines containing Aconitum species; however, its underlying mechanism remains unclear.<BR><B>OBJECTIVE: </B>The objective of this study is to elucidate the functions of P-glycoprotein (P-gp) in regulating the efficacy, toxicity, and pharmacokinetics of YAC.<BR><B>METHODS: </B>The efflux function of P-gp on YAC was explored by using Caco-2 monolayers in combination with the P-gp inhibitor verapamil. The impact of P-gp on regulating the analgesic and anti-inflammatory effects, acute toxicity, tissue distribution, and pharmacokinetics of YAC was determined via male Mdr1a gene knocked-out mice and wild-type FVB mice.<BR><B>RESULTS: </B>The presence of verapamil significantly decreased the efflux ratio of YAC from 20.41 to 1.07 in Caco- 2 monolayers (P < 0.05). Moreover, oral administration of 0.07 and 0.14 mg/kg YAC resulted in a notable decrease in writhing times in Mdr1a-/- mice by 23.53% and 49.27%, respectively, compared to wild-type FVB mice (P < 0.05). Additionally, the deficiency of P-gp remarkably decreased the half-lethal dose (LD50) of YAC from 2.13 to 0.24 mg/kg (P < 0.05). Moreover, the concentrations of YAC in the tissues of Mdr1a-/- mice were statistically higher than those in wild-type FVB mice (P < 0.05). Particularly, the brain accumulation of YAC in Mdr1a-/- mice significantly increased by 12- and 19-fold, respectively, after oral administration for 30 and 120 min, when compared to wild-type FVB mice (P < 0.05). There were no significant differences in the pharmacokinetic characteristics of YAC between Mdr1a-/- and wild-type FVB mice.<BR><B>CONCLUSIONS: </B>YAC is a sensitive substrate of P-gp. The absence of P-gp enhances the analgesic effect and toxicity of YAC by upregulating its brain accumulation. Co-administration with a P-gp inhibitor may lead to severe YAC poisoning.