A validated RP-HPLC method for the determination of rosuvastatin in presence of sacubitril/valsartan in rat plasma: Application to in vivo evaluation of OATP-mediated drug interaction potential between rosuvastatin and sacubitril/valsartan

Entresto® tablets (sacubitril/valsartan combination) were recently approved by FDA to reduce the risk of cardiovascular death in patients with chronic heart failure. Entresto® is usually administered in conjunction with rosuvastatin. Sacubitril inhibits organic anion-transporting polypeptides (OATP) responsible for the uptake of rosuvastatin into human hepatocytes. The aim of this investigation was to evaluate OATP-mediated drug interaction potential between rosuvastatin and sacubitril/valsartan upon co-administration in rats. An RP-HPLC method was developed and validated for determination of rosuvastatin in rat plasma in presence of sacubitril and valsartan. A Zorbax Eclipse C18 Cyano column was used as stationary phase and acidified water (pH 3, adjusted with acetic acid): acetonitrile (55: 45, v/v) as mobile phase at flow rate 1 ml/min, using UV detection at λ 254 nm. Liquid-liquid extraction was applied for drug extraction from plasma, using diethyl ether: dichloromethane (70: 30, v/v). The method was linear over concentration range of 2-200 μg/ml. Coefficient of variation ranged from 0.033 to 3.28% and 0.24 to 3.84% for intraday and interday precision, respectively. The accuracy values were found to be between 96.57 and 105.39%. The method was successfully applied to in vivo pharmacokinetic study in which rosuvastatin was estimated in plasma of rats given an oral dose of sacubitril/valsartan and an interperitoneal dose of rosuvastatin. The pharmacokinetic parameters were calculated. As a conclusion, sacubitril/valsartan significantly increased rosuvastatin bioavailability in rats, thus a potentially significant drug-drug interaction must be considered in patients treated with entresto® tablets in conjunction with rosuvastatin.