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

Abstract

SummaryThe 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 enaJapril. 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 (GCIMS). There was no significant difference in the maximum plasma concentrations (C max ) of RS-5139 between the nephrectomised (243.3 Ilg/L) and control rats (342.8Ilg/L). On the other hand, the Cmax of enalaprilat in nephrectomised rats was significantly higher (399.3IlgIL) than in the control group (158.6Ilg/L; p < 0.05). Biliary excretion of RS-5139 was up to 79.2 and 8l.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.

Comparison of the renal effects of different angiotensin-converting enzyme inhibitors in patients with chronic renal diseases

“…In addition, in order to exclude the effects of renal dysfunction on the accumulation of active metabolites of ACE-I, the dose of ACE-I was adjusted for differences in metabolism caused by impaired renal function. Because five of the six ACE-Is (except for temocapril) used in this study are mainly excreted from the kidney, 16 and temocapril is almost equally degraded by the liver and kidney 17,18 (Table 1), the dose of ACE-I administered was adjusted according to the 24-h Ccr with the formula shown in Fig. 1.…”

“…The doses of the ACE-Is were adjusted according to the patient's renal function, because the renal functions of the patients varied widely. Five of the ACE-Is i.e., all except temocapril, are degraded mostly in the kidney, 16 and temocapril is degraded in both kidney and liver almost equally, 17,18 and therefore we adjusted target doses of ACE-I according to 24-h Ccr, in order to equalize the inhibitory effect of blood ACE activity ( Table 1, Fig. 1).…”

“…Characteristics of ACE-Is used in this study13,[16][17][18] ACE-I, Angiotensin-converting enzyme inhibitor; MW, molecular weightTable 2. Clinical profiles of the patients in the six groups in the study…”

Temocapril, A Novel Angiotensin‐Converting Enzyme Inhibitor with Preferential Biliary Excretion

“…Similarly, surgical impairment of renal excretory function has been shown to greatly increase plasma diacid concentrations after oral administration of enalapril, but not temoCapri1 (5). Taken together, these data suggest that temocapril, unlike other ACE inhibitors, is excreted primarily by the biliary route.…”

“…The single-dose pharmacokinetics of temocapril were studied in partially nephrectomized rats and compared with those of enalapril (5). Biliary excretion of temocaprilat was up to 79.2 and 8 1.8% in the control and nephrectomized groups, whereas the corresponding values for enalaprilat were only 7.7 and 12.2%.…”