Sensitive UHPLC–MS/MS quantitation and pharmacokinetic comparisons of multiple alkaloids from Fuzi- Beimu and single herb aqueous extracts following oral delivery in rats

Aconiti Lateralis Radix Praeparata- Fritillariae Thunbergii bulbus, namely Fuzi- Beimu in Chinese, is a classic herb pair whose combined administration was prohibited according to the rule of “Eighteen antagonisms”. However, incompatibility of Fuzi and Beimu has become controversial because of the application supported by many recorded ancient prescriptions and increasing modern researches and clinical practice. The present study aimed to investigate the pharmacokinetic differences of multiple alkaloids from Fuzi- Beimu and the single herb aqueous extracts following oral delivery in rats. Twelve alkaloids including aconitine, mesaconitine, hypaconitine, benzoylaconitine, benzoylmesaconitine, benzoylhypacoitine, neoline, fuziline, talatisamine, chasmanine, peimine and peimisine in rat plasma were simultaneously quantitated by using sensitive ultra-high performance liquid chromatography- tandem mass spectrometry (UHPLC–MS/MS), with the method developed and fully validated. Plasma concentrations of the twelve alkaloids after administration were determined and pharmacokinetic parameters were compared. Significant differences were observed for all alkaloids except aconitine, mesaconitine and benzoylaconitine for Fuzi- Beimu group in comparison with the single herb group. AUC0-t and T1/2 of hypaconitine were increased significantly. AUC0-t and Cmax were increased and Tmax decreased significantly for benzoylmesaconitine and benzoylhypacoitine. Fuziline showed significantly increased AUC0-t, Cmax and Tmax. T1/2 of neoline was notably increased. T1/2 and Tmax were significantly elevated for talatisamine while Cmax decreased. Tmax of chasmanine was significantly increased and Cmax decreased. Extremely significant increase of Tmax was found for peimisine, and significant increase of T1/2 for peimine. Results revealed that combined use of Fuzi and Beimu significantly influenced the system exposure and pharmacokinetic behaviors of multiple alkaloids from both herbs, indicating herb- herb interaction between Fuzi and Beimu.