Studies on the Incompatibility between Bulbus fritillariae and Radix aconiti praeparata Based on the P-gp

Bulbus fritillariae and Radix aconiti praeparata are an incompatible herbal pair in the traditional Chinese medicine theory “eighteen incompatible medicaments,” and they should not be used simultaneously in clinical treatment for safety. This study aimed to investigate the incompatibility mechanism between Bulbus fritillariae and Radix aconiti praeparata based on their interaction with P-glycoprotein (P-gp). The interaction between Bulbus fritillariae and Radix aconiti praeparata during in vitro decocting as well as in vivo absorption was investigated by determining the dry extract yield and by rat single-pass intestinal perfusion (SPIP) model. Inhibition of different species of Bulbus fritillariae on P-gp function was examined using the SPIP model. The mRNA and protein expression of P-gp was determined by PCR and western blotting. The active ingredients of Bulbus fritillariae were predicted and screened for inhibiting P-gp activity by Schrodinger’s molecular docking and MDR1-MDCK cell transport study, respectively. Mediation of monoester alkaloids in Radix aconiti praeparata by P-gp was predicted and examined using Schrodinger’s molecular docking and SPIP experiment, respectively. In the results, when Radix aconiti praeparata was combined with Bulbus fritillariae, the toxic ingredient benzoylmesaconine in Radix aconiti praeparata displayed higher intestinal permeability, whereas the toxic ingredients showed no significant difference during the in vitro decoction process. Bulbus fritillariae thunbergii inhibited both the P-gp function and expression; in contrast, Bulbus fritillariae cirrhosae inhibited the function only. Alkaloids including peimine, peimisine, and imperialine were the active ingredients for inhibiting P-gp activity. Benzoylmesaconine in Radix aconiti praeparata was the substrate of P-gp.

Paeoniflorin and albiflorin regulate P-gp-mediated aconitine and hypaconitine transport through an Madin Darby canine kidney-multi drug resistance protein 1 cell model

Aconitine and hypaconitine are the main active ingredients of Radix Aconiti, paeoniflorin and albiflorin are the primary components of Radix Paeoniae Alba. Both Radix Aconiti and Radix Paeoniae Alba are herbs that are commonly used in traditional Chinese medicine. This study sought to explore the mechanistic transport of aconitine and hypaconitine across MDCK-MDR1 cells and to assess the effect of paeoniflorin and albiflorin on aconitine and hypaconitine transmembrane transport as a potential attenuation mechanism. Drug cytotoxicity was tested via the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and transport studies were performed in both directions. The effects of drugs on P-gp ATPase activity, P-gp efflux function, MDR1 mRNA and P-gp expression were evaluated in MDCK-MDR1 cells. Aconitine and hypaconitine treatment with the verapamil could significantly decrease the efflux rate (ER). The ER of aconitine and hypaconitine were significantly increased with the coadministration of paeoniflorin and albiflorin, suggesting that paeoniflorin and albiflorin can promote the efflux of these two alkaloids. Aconitine and hypaconitine can induce P-gp enzymatic activity, inhibit P-gp-mediated efflux, and downregulate the expression of P-gp protein to produce cytotoxic effects. When treatment in combination with paeoniflorin and albiflorin, it could stimulated P-gp ATPase activity, increasing mRNA expression, enhance P-gp efflux function, and upregulate P-gp protein expression.

The toxicology and detoxification of Aconitum: traditional and modern views

Aconitum carmichaeli Debx.-derived herbal medicine has been used for anti-inflammation and anti-arrhythmia purpose for more than two thousand years. It is processed into Chuanwu (Radix Aconiti praeparata) and Fuzi (Radix Aconiti lateralis praeparata) in Traditional Chinese Medicine, which are two useful drugs but with toxic properties. There have been patients poisoned by accidental ingestion of Aconitum plants or misuse of the herbal drug, and this is of great concern to study in-depth. In this review, we provided the traditional and contemporary practice of using Aconitum herbs as medicine, from functions, processing methods to toxicity in ethnomedicine aspects to discuss the underlying connections of traditional and modern understanding on the toxicity of Aconitum plants. We summarized the functions and toxicology of the herbal drugs are analyzed from chemical and clinical aspects, with the help of traditional and modern knowledge of medicine. The medicinal doses and lethal doses determined by researches are summarized, and the usage and processing methods are updated and reviewed in the modern view. In addition, clinical management of poisoned cases using western medicine is discussed. This review provides insights and awareness of safety when using Aconitum-derived herbal medicine, and the application of modern scientific knowledge to optimize the detoxification processes. We suggest the possibility to renew the current standard processing method from the official Pharmacopoeia all over the world.

Crude Radix Aconiti Lateralis Preparata (Fuzi) with Glycyrrhiza Reduces Inflammation and Ventricular Remodeling in Mice through the TLR4/NF-κB Pathway

Radix Aconiti Lateralis Preparata (Fuzi) is a traditional Chinese medicine. Its alkaloids are both cardiotonic and cardiotoxic; however, the underlying mechanisms are unclear. Compatibility testing and processing are the primary approaches used to reduce the toxicity of aconite preparations. The purpose of this study was to compare the effects of crude Fuzi (CFZ), CFZ combined with Glycyrrhiza (Gancao) (CFZ+GC), and prepared materials of CFZ (PFZ) on heart failure (HF) in C57BL/6J mice and explore the potential mechanisms of action of CFZ. Transverse aortic constriction (TAC) was used to generate the HF state, and CFZ (1.5 g·mL−1), PFZ (1.5 g·mL−1), or CFZ+GC (1.8 g·mL−1) was orally administered to the HF-induced mice daily. For the subsequent 8 weeks, hemodynamic indicators, ventricular pressure indices, and mass indices were evaluated, and histopathological imaging was performed. CFZ, CFZ+GC, and PFZ significantly improved left ventricular function and structure and reduced myocardial damage. CFZ+GC was more effective than CFZ and PFZ, whereas CFZ had higher toxicity than CFZ+GC and PFZ. CFZ and CFZ+GC attenuated ischemia-induced inflammatory responses and also inhibited Toll-like receptor-4 (TLR4) and nuclear factor kappa beta (NF-κB) action in the heart. Moreover, mass spectrometry analysis revealed a decrease in the levels of toxic components of CFZ+GC, whereas those of the protective components were increased. This study suggested that GC reduces the toxicity and increases the efficacy of CFZ on HF induced by TAC. Furthermore, GC+CFZ reduces the risk of HF by ameliorating the inflammation response, which might be partially related to the inhibition of the TLR4/NF-κB pathway.