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

摘要

Entresto (R) tablets (sacubitril/valsartan combination) were recently approved by FDA to reduce the risk of cardiovascular death in patients with chronic heart failure. Entresto (R) 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 C-18 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 lambda 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 mu g/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 (R) tablets in conjunction with rosuvastatin.