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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.

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