The effect of candesartan on the pharmacokinetics of enalaprilat in nephrotic rats.

BACKGROUND AND OBJECTIVES The adverse reactions in combination of angiotensin-converting enzyme inhibitors (ACEIs) and Ang II receptor blockers (ARBs) were severer than that in monotherapy for patients with nephropathy. The effect of candesartan on pharmacokinetics of enalaprilat in nephrotic rats was investigated to make references for the clinical therapy in patients with nephropathy to avoid related adverse effects. MATERIALS AND METHODS Nephrotic rats were prepared by adriamycin injection. Control group and one nephrotic group received enalapril alone, another nephrotic group received enalapril and candesartan simultaneously. Blood samples were drawn at time points after a single oral administration. The concentration of enalaprilat was determined using LC-MS/MS. RESULTS Compared with control group and nephrotic group received enalapril alone respectively, Tmax of enalaprilat in nephrotic group received both enalapril and candesartan cilexetil prolonged about 21.43% and 6.224%, respectively; AUC(0-t) increased by 185.3% and 60.63%, respectively; Cmax increased by 219.4% and 56.64%, respectively; t1/2 increased by 163.7% and 30.05%, respectively; CL/F reduced by 65.12% and 40.78%, respectively. There were no significant differences of the V1/F of enalaprilat between three groups. The CL/F and t1/2 of enalaprilat showed significant correlations with serum creatinine (Scr) respectively (r = -0.7502; r = 0.5626). DISCUSSION The combination with candesartan in nephrotic rats significantly changed the pharmacokinetics of enalaprilat, showing increased accumulation and decreased elimination. In view of these findings, we should lower dosage and prolong dosing interval for nephrotic patients in the combination of enalapril and candesartan.