Enhancement of potassium-, and angiotensin II-stimulated aldosterone production by the calcium chelator EGTA in bovine adrenal glomerulosa cells in vitro

OBJECTIVE: The aim of this study was to determine the influence of renal impairment on the single-dose pharmacokinetics of temocapril and its pharmacologically active metabolite, temocapril diacid. METHODS: A single oral dose of 20 mg temocapril hydrochloride was given after an overnight fast to eight healthy (control) subjects (group A, n = 8) with a mean baseline creatinine clearance (CLCR) of 115.2 ml.min-1 and to three groups of patients with decreased renal function (mean CLCR 56.9 ml in group B, n = 8, 30.0 ml.min-1 in group C, n = 8 and 15.4 ml.min-1 in group D, n = 5). RESULTS: The mean peak concentration and median time to peak concentration for both temocapril and its diacid metabolite as well as the man area under the curve (AUC0-infinity) for temocapril did not differ significantly between groups. The mean AUC0-infinity for temocapril diacid increased only two- to threefold from group A to D. The mean terminal elimination half-life (t1/2) for temocapril diacid was prolonged in subjects with impaired renal function. However, prolongation of mean t1/2 and increase in AUC0-infinity did not parallel the decrease of mean renal clearance for temocapril diacid. CONCLUSION: The results suggest the existence of an alternative pathway in addition to the renal excretion of temocapril, e.g. via the bile. This pathway substantially contributes to the elimination of the active metabolite, temocapril diacid, in patients with decreased renal function. Nonetheless, to avoid any risks, the dose of temocapril hydrochloride in patients with moderate to severe renal impairment should be reduced.