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Volume 25, Issue 5
  • ISSN: 1389-2002
  • E-ISSN: 1875-5453

Abstract

Background

Yunaconitine (YAC) is a hidden toxin that greatly threatens the life safety of patients who are prescribed herbal medicines containing species; however, its underlying mechanism remains unclear.

Objective

The objective of this study is to elucidate the functions of P-glycoprotein (P-gp) in regulating the efficacy, toxicity, and pharmacokinetics of YAC.

Methods

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 male Mdr1a gene knocked-out mice and wild-type FVB mice.

Results

The presence of verapamil significantly decreased the efflux ratio of YAC from 20.41 to 1.07 in Caco-2 monolayers ( < 0.05). Moreover, oral administration of 0.07 and 0.14 mg/kg YAC resulted in a notable decrease in writhing times in -/- mice by 23.53% and 49.27%, respectively, compared to wild-type FVB mice ( < 0.05). Additionally, the deficiency of P-gp remarkably decreased the half-lethal dose (LD) of YAC from 2.13 to 0.24 mg/kg ( < 0.05). Moreover, the concentrations of YAC in the tissues of mice were statistically higher than those in wild-type FVB mice ( < 0.05). Particularly, the brain accumulation of YAC in mice significantly increased by 12- and 19-fold, respectively, after oral administration for 30 and 120 min, when compared to wild-type FVB mice ( < 0.05). There were no significant differences in the pharmacokinetic characteristics of YAC between and wild-type FVB mice.

Conclusion

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.

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Role of P-glycoprotein in Regulating the Efficacy, Toxicity and Pharmacokinetics of Yunaconitine
Current Drug Metabolism 25, 317 (2024); https://doi.org/10.2174/0113892002302427240801072910
/content/journals/cdm/10.2174/0113892002302427240801072910
/content/journals/cdm/10.2174/0113892002302427240801072910
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  • Article Type:     Research Article
Keyword(s): brain accumulation; edema; efficacy; P-glycoprotein; toxicity; Yunaconitine

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