Assessment of drug–drug interaction of dapagliflozin with LCZ696 based on an LC–MS/MS method

Abstract

AbstractThe co‐administration of dapagliflozin (DPF) and sacubitril/valsartan (LCZ696) has emerged as a promising therapeutic approach for managing heart failure. Given that DPF and LCZ696 are substrates for P‐glycoprotein, there is a plausible potential for drug–drug interactions when administered concomitantly. To investigate the pharmacokinetic changes when these drugs are co‐administered, we have established and validated a liquid chromatography–tandem mass spectrometry (LC–MS/MS) method capable of simultaneously detecting DPF, LBQ657 (the active metabolite of sacubitril) and valsartan in rat plasma. This method has demonstrated selectivity, sensitivity, and accuracy. Drug–drug interactions were examined by the LC–MS/MS method. The mechanisms were investigated using everted intestinal sac models and Caco‐2 cells. The results showed that DPF significantly increased the area under the curve (AUC(0–t)) (3,563.3 ± 651.7 vs. 7,146.5 ± 1,714.9 h μg/L) of LBQ657 (the active metabolite of sacubitril) and the AUC(0–t) (24,022.4 ± 6,774.3 vs. 55,728.3 ± 32,446.3 h μg/L) of valsartan after oral co‐administration. Dapagliflozin significantly increased the amount of LBQ657 and valsartan in intestinal sacs by 1‐ and 1.25‐fold at 2.25 h. Caco‐2 cell uptake studies confirmed that P‐glycoprotein is the transporter involved in this interaction. This finding enhances the understanding of drug–drug interactions in the treatment of heart failure and provides a guidence for clinical therapy.