SINGLE-DOSE PHARMACOKINETICS OF TEMOCAPRIL (CS-622), A NOVEL ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITOR, IN PARTIALLY NEPHRECTOMIZED RATS

The single dose pharmacokinetics of temocapril, a prodrug type angiote nsin converting enzyme (ACE) inhibitor with a thiazepin ring, were stu died 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 a nd 18.6 mg/dl, respec- tively). Concentrations of RS-5139 and enalapri lat, the active metabolites of temocapril and enalapril, respectively, in the plasma, bile and urine were measured by the ACE inhibition ass ay or a gas chromatography-mass spectrometry system (GC/MS). There was no significant difference in the maximum plasma concentrations (C-max ) of RS-5139 between the nephrectomised (243.3 mu g/L) and control rat s (342.8 mu g/L). On the other hand, the C-max of enalaprilat in nephr ectomised rats was significantly higher (399.3 mu g/L) than in the con trol group (158.6 mu g/L; p < 0.05). Biliary excretion of RS-5139 was up to 79.2 and 81.8% in the control and nephrectomised groups, respect ively, 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 c ontrol and nephrectomised rats, respectively, whereas the correspondin g 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.