Effects of diammonium glycyrrhizinate on the pharmacokinetics of aconitine in rats and the potential mechanism

Abstract

1. The objective of this study was to investigate the effects of diammonium glycyrrhizinate on the pharmacokinetics of aconitine in rats and the potential mechanism. 2. After oral administration of diammonium glycyrrhizinate (50 mg kg(-1)), the peak plasma concentration (C(max)), area under the plasma concentration-time curve from zero to time tau (AUC(0-tau)), and absolute bioavailability of aconitine (0.2 mg kg(-1)) significantly increased 1.64-, 1.63- and 1.85-fold, respectively, but there was no significant change in half life (t(1/2)) or clearance (CL). In the other two routes of administration via the tail vein and hepatic portal vein, diammonium glycyrrhizinate (15 mg kg(-1)) did not affect any of the pharmacokinetic parameters of aconitine (0.02 mg kg(-1)). Thus, diammonium glycyrrhizinate can enhance the absorption of aconitine, leading to higher oral bioavailability and plasma levels, but it does not influence its elimination. 3. Moreover, an in vitro everted gut sac model and Ussing chamber model were used to investigate the potential mechanism. Results from bidirectional transport and inhibition studies demonstrated that P-glycoprotein was the main efflux transporter involved in the absorption of aconitine in rats. The absorption enhancement effect of diammonium glycyrrhizinate should be mainly attributed to inhibiting the activity of P-glycoprotein rather than to the influence on the paracellular or transcellular transport.

Pharmacokinetics of aconitine as the targeted marker of Fuzi (Aconitum carmichaeli) following single and multiple oral administrations of Fuzi extracts in rat by UPLC/MS/MS

“…After accounting for dose, these C max and t max values after oral administration were consistent with those reported by Chen et al (2009) andTazawa et al (2003). However, the absolute bioavailability (F %) calculated in the experiment is about one-third to one-fifth of the value reported by Chen and 4-fold to 8-fold of the value reported by Tazawa.…”

“…The low plasma concentrations of aconitine in rats could have been significantly affected by the different analytical methods resulting in the above mentioned behaviour. According to the in vivo and in vitro data published, the low oral bioavailability of aconitine in rat is mainly due to the efflux through the P-glycoprotein but unrelated to the intestinal metabolic enzymes (Chen et al, 2009) in rats. Further research on the mechanism of low bioavailability should be conducted.…”

Relative Quantification of the Metabolite of Aconitine in Rat Urine by LC-ESI-MS/MS and Its Application to Pharmacokinetics

“…In addition, since aconitum alkaloids are very unstable and decomposed fast in the human body, 3 metabolite studies are helpful to understand the medication safety, toxification and detoxification mechanism. Earlier publications have described methods for aconitine determination in biological samples, [4][5][6][7][8][9][10] and the identification of metabolites. [11][12][13] This paper reports on a pharmacokinetics study of aconitine metabolite in rat urine after oral administration for the first time, using a simple and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.…”

Panax ginseng inhibits intestinal absorption of toxic Aconitum carmichaeli alkaloids in Vitro

“…To address this, a few studies have been conducted on the absorption of monomers and their effects. (9)(10)(11)(12)(13) In CM Aconitum carmichaeli extract is used more widely than the alkaloid monomer, and in many cases, it is co-administrated with other herbs to reduce its toxicity or to obtain purportedly synergistic effects. (1) At this time, however, little evidence is available to describe pharmacokinetic behaviors of alkaloids acting individually or as a combination product.…”