Single Dose Pharmacokinetics of Temocapril (CS-622), a Novel Angiotensin Converting Enzyme (ACE) Inhibitor, in Partially Nephrectomised Rats

The single dose pharmacokinetics of temocapril, a prodrug type angiotensin converting enzyme (ACE) inhibitor with a thiazepin ring, were studied in nephrectomised rats and compared with those of enalapril. The nephrectomised rats had much higher serum levels of creatinine (1.1 mg/dl) and blood urea nitrogen (73.5 mg/dl) than the control rats (0.6 and 18.6 mg/dl, respectively). Concentrations of RS-5139 and enalaprilat, the active metabolites of temocapril and enalapril, respectively, in the plasma, bile and urine were measured by the ACE inhibition assay or a gas chromatography-mass spectrometry system (GC/MS). There was no significant difference in the maximum plasma concentrations (Cmax) of RS-5139 between the nephrectomised (243.3 μg/L) and control rats (342.8 μg/L). On the other hand, the Cmax of enalaprilat in nephrectomised rats was significantly higher (399.3 μg/L) than in the control group (158.6 μg/L; p<0.05). Biliary excretion of RS-5139 was up to 79.2 and 81.8% in the control and nephrectomised groups, respectively, whereas the corresponding values for enalaprilat were only 7.7 and 12.2%. Urinary excretion of RS-5139 was only 4.7 and 3.8% in the control and nephrectomised rats, respectively, whereas the corresponding values for enalaprilat were 48.9 and 54.1%. These results show that a single dose of temocapril is preferentially excreted in bile and its elimination was unaffected by impaired renal function.