temocapril-hydrochloride and Kidney-Diseases

The aim of this study was to determine the potential influence of renal impairment on the pharmacokinetics of temocapril and its pharmacologically active diacid metabolite, temocaprilat.. Non-compartmental pharmacokinetics were assessed in four groups of hypertensive patients (n=8 per group, four investigational centres) with normal (creatinine clearance determined via 24 h urine sampling, CL[CR], > or = 60 ml min-1) and impaired renal function (CL[CR] 40-59, 20-39, < 20 ml min-1) after 14 once daily oral doses of 10 mg temocapril hydrochloride.. For temocapril, there were no statistically significant differences in median tmax or mean Cmax, AUC(SS), t1/2,Z, CL/F between the four groups. Renal clearance, CL(R), for temocapril showed a linear decreasing trend with decreasing CL(CR) [mean (s.d.): 32.2 (10.7) to 3.7 (3.0) ml min-1]. Steady-state for temocaprilat was reached on day 5. For temocaprilat, no statistically significant differences in mean Cmax or median tma were detected. With decreasing mean CL(CR), mean AUC(SS) for temocaprilat increased statistically significantly although only 2.4-fold [mean (s.d.): 2115 (565) to 4989 (2338) ng ml-1 h] and t1/2,Z was prolonged [mean (s.d.): 15.2 (1.2) to 20.0 (7.5) h]. CL(R) for temocaprilat showed a linear decreasing trend with decreasing CL(CR) [mean (s.d.): 20.2 (4.3) to 3.0 (1.8) ml min-1].. These results indicate that impaired renal function has only a limited effect on the pharmacokinetics of temocapril and its active metabolite, temocaprilat. This may be attributed to the dual, i.e. renal and biliary, elimination pathway of the drug.

Topics: Adult; Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Area Under Curve; Creatinine; Female; Humans; Kidney Diseases; Male; Middle Aged; Thiazepines

We examined the effect of temocapril (Tem), an angiotensin converting enzyme inhibitor (ACEI), on the cyclosporine-induced nephrotoxicity (CsA-NT) in rats.. Male Wistar rats were used. Group 1 (G1) received a medium (i.e. olive oil) only, group 2 (G2) received CsA (30 mg./kg./d) only, group 3 (G3) received both CsA (30 mg./kg./d) and Tem (80 micrograms./kg./d), and group 4 (G4) received Tem (80 micrograms./kg./d) only. Each group consisted of 5 animals. Drugs were given orally for fourteen days. Then, renal cortical blood flow (RCBF) and concentrations of serum creatinine (S-Cr), serum potassium (S-K), whole blood CsA (WB-CsA), serum aldosterone (Ald), and plasma renin activity (PRA) were measured. The creatinine clearance (CCr) was also calculated. Kidneys were processed to the light microscopic examination with Bowie stain, and the size of the renin granules (S-RGs) was estimated by an image analysis system.. G2 showed a decrease of RCBF (p < 0.01), an increase of S-Cr (p < 0.01), a decrease of CCr (p < 0.01), an increase of S-K (p < 0.05), and an increase of S-RGs (p < 0.01). Compared with G2, G3 showed significant improvement in RCBF (p < 0.01) and S-Cr (p < 0.05), but still showed significant impairments in all indices (p < 0.01 or p < 0.05, vs control). G4 showed no remarkable changes comparing with G1, except a significant (p < 0.01, vs. control) increase of S-K. G3 showed additional effect on the increase of S-K (p < 0.01, vs. control and G2). Tem showed no significant influence on the WB-CsA level. The serum Ald and PRA levels were not significantly changed by these drugs.. These data are compatible with the hypothesis that the vasoconstriction of the afferent arterioles (AAs) is a principal mechanism of CsA-NT. The increase of RGs may be the result of both increased production and inhibited secretion of renin.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cyclosporine; Kidney Diseases; Male; Rats; Rats, Wistar; Thiazepines