A review: Pharmacokinetics and pharmacology of aminoalcohol-diterpenoid alkaloids from Aconitum species

Ethnopharmacological relevance: Aconitum medicinal materials, such as Aconitum carmichaelii Debeaux (Chinese: Wutou/(sic)) and Aconitum kusnezoffii Reichb. (Chinese: Caowu/(sic)), are a kind of important Traditional Chinese Medicine (TCM) with great medicinal value. Statistics show that there are over 600 efficient TCM formulations comprising Aconitum medicinal materials. But high toxicity limits their clinical application. Clinically, the Aconitum medicinal materials must undergo a complex processing process that includes soaking, steaming, and boiling with pharmaceutical excipients, which makes highly toxic ester diterpenoid alkaloids are hydrolyzed to form less toxic aminoalcohol-diterpenoid alkaloids (ADAs). Aim of the study: This review aims to summarize the pharmacokinetic and pharmacological activities of lowtoxicity ADAs, providing a reference for future ADAs research and drug development. Materials and methods: Accessible literature on ADAs published between 1984 and 2022 were screened and obtained from available electronic databases such as PubMed, Web of Science, Springer, Science Direct and Google Scholar, followed by systematic analysis. Results: ADAs are secondary products of plant metabolism, widely distributed in the Aconitum species and Delphinium species. The toxicity of ADAs as pharmacodynamic components of Aconitum medicinal materials is much lower than that of other diterpenoid alkaloids due to the absence of ester bonds. On the one hand, the pharmacokinetics of ADAs have received little attention compared to other toxic alkaloids. The research primarily focuses on aconine and mesaconine. According to existing studies, ADAs absorption in the gastrointestinal tract is primarily passive with a short T-max. Simultaneously, efflux transporters have less impact on ADAs absorption than non-ADAs. After entering the body, ADAs are widely distributed in the heart, liver, lungs, and kidney, but less in the brain. Notably, aconine is not well metabolized by liver microsomes. Aconine and mesaconine are excreted in urine and feces, respectively. ADAs, on the other hand, have been shown to have a variety of pharmacological activities, including cardiac, analgesic, anti-inflammatory, anti-tumor, antioxidant, and regenerative effects via regulating multiple signaling pathways, including Nrf2/ARE, PERK/eIF2a/ATF4/ Chop, ERK/CREB, NF-.B, Bcl-2/Bax, and GSK3 ss/ss-catenin signaling pathways. Conclusions: ADAs have been shown to have beneficial effects on heart disease, neurological disease, and other systemic diseases. Moreover, ADAs have low toxicity and a wide range of safe doses. All of these suggest that ADAs have great potential for drug development.