Drug-drug Interaction Between Chlorpheniramine And Saikosaponin Mediated By CYP2D6in Vivo And Vitro In Rats

Chlorpheniramine and proprietary Chinese medicine are oftencombination used to increase efficacy in treatment of cold diseases, whichgreatly increased the risk of drug-drug interactions. Previrously, peopleoften focus on direct interaction between drug compatibility and mainingredients, but the effect of pharmaceutical ingredients itself or differentcomponents on biological activity of drug-metabolizing enzymes wereignored. Metabolic activity changes of CYPs play a crucial role inproduction of drug efficacy and side effects. Therefore, investigation ofherb and drug compatibility by the CPYs in vivo metabolic enzyme-mediated interaction and its mechanism has important practicalsignificance in clinical. Chlorpheniramine was metabolized by CYP2D6invivo and Bupleurum was also a main ingredient in anti-cold Chinesemedicines. When combination used of this two drugs, whether the mainingredient in Bupleurum inhibite the activity of CYP2D6, then mediateddrug-drug interactions have not been reported in previous studies.This work examined the potential for the metabolism-based drug interaction between chlorpheniramine and saikosaponins. Thepharmacokinetic parameters of chlorphenamine were estimated. The meanAUC（0-∞）was significantly increased from0.980±0.047to1.245±0.068μg ml*h^-1, the C_maxwas significantly increased from0.923±0.044to1.391±0.039μg ml^-1, and apparent oral total body clearance （CLz/F） significantlydecreased from20.493±1.032to16.128±0.837L/h/kg. Otherpharmacokinetic parameters (Tmax, T_1/2) showed no significant changecompared with the control. Saikosaponins a and d are all significantlyagainst to the active of CYP2D6in vitro, saikosaponin a was a weakmixed-type inhibitor of CYP2D6activities (IC₅₀=112.8μmol L^-1,Ki=104.31μmol L^-1). Saikosaponin d was a potent competitive inhibitor ofCYP2D6activities (IC150=21.7μmol L-, Ki=38.08μmol L^-1).In this study, we investigated the effect of the pharmacokinetics ofchlorpheniramine, after co-administration of oral the extract of Radixbupleuri and oral chlorpheniramine in rats; and further validated theinhibition effect of CYP2D6by saikosaponins a and d, there may be highrisk of adverse drug reactions caused. It prompted that theco-administration of the two types drugs in the clinical should be avoided.The findings have important guiding significance for rational drug use.