SINGLE-DOSE PHARMACOKINETICS OF TEMOCAPRIL AND TEMOCAPRIL DIACID IN SUBJECTS WITH VARYING DEGREES OF RENAL IMPAIRMENT

Objective: The aim of this study was to determine the influence of ren al impairment on the single-dose pharmacokinetics of temocapril and it s pharmacologically active metabolite, temocapril diacid. Methods: A s ingle oral dose of 20 mg temocapril hydrochloride was given after an o vernight fast to eight healthy (control) subjects (group A, n = 8) wit h a mean baseline creatinine clearance (CLCR) of 115.2 ml min(-1) and to three groups of patients with decreased renal function (mean CLCR 5 6.9 ml in group B, n = 8, 30.0 ml.min(-1) in group C, n = 8 and 15.4 m l.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 mean area under the curve (AUC(0-infinity)) for temocapril did not differ significantly between groups. The mean A U(0-infinity) for temocapril diacid increased only two-to threefold fr om group A to D. The mean terminal elimination half-life (t1/2) for te mocapril diacid was prolonged in subjects with impaired renal function . However, prolongation of mean t1/2 and increase in AU(0-infinity) di d not parallel the decrease of mean renal clearance for temocapril dia cid. Conclusion: The results suggest the existence of an alternative p athway 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 rena l function. Nonetheless, to avoid any risks, the dose of temocapril hy drochloride in patients with moderate to severe renal impairment shoul d be reduced.