Temocapril is a novel ACE inhibitor that is cleared via dual excretion routes in humans. Borderline or mildly hypertensive patients with normal renal function [group 1, creatinine clearance (CLCR) > 70 ml/min (4.2 L/h), n = 12], moderate renal impairment [group 2, CLCR 30 to 70 ml/min (1.8 to 4.2 L/h), n = 12] or severe renal impairment [group 3, CLCR < 30 ml/min (1.8 L/h), n = 12] received a single oral dose of either temocapril 1 mg (n = 6, each group) or enalapril 5mg (n = 6, each group). These 2 drugs gave similar values for the area under the plasma concentration-time curve (AUC) of the active diacids. The maximum plasma concentration of enalapril diacid was increased 2- and 6-fold in moderate and severe renal impairment, respectively, whereas that of temocapril diacid was not altered. The AUC of enalapril diacid increased 13-fold at CLCR values < 30 ml/min, but that of temocapril diacid increased only 2-fold. The duration of plasma ACE inhibition due to enalapril was greatly prolonged by the impairment of renal function, whereas that due to temocapril was affected very little. Urinary recovery of temocapril diacid was decreased markedly in patients with severe renal dysfunction, most probably because the diacid was excreted through the biliary route. On the other hand, urinary recovery of enalapril diacid remained fairly high even in patients with severe renal impairment, because of extremely high plasma diacid concentrations resulting from the lack of biliary excretion. These observations suggest that temocapril is beneficial in the treatment of hypertension in patients with severely impaired renal function.
SummaryThe single dose pharmacokinetics of temocapril, a novel prodrug type angiotensin converting enzyme (ACE) inhibitor with preferential biliary excretion, were evaluated in 6 patients maintained on haemodialysis and in 1 patient on continuous ambulatory peritoneal dialysis (CAPD). In a crossover design, each haemodialysis patient received a single oral dose of temocapril 1mg after breakfast on two occasions, on dialysis and nondialysis days, at an interval of 1 week. The CAPD patient received a single oral dose of temocaprillmg. Plasma concentrations of temocapril and its active metabolite (diacid) and ACE activity were determined after drug administration. Area under the plasma concentration-time curves (AUC) in haemodialysis patients on the nondialysis day were significantly greater than those in patients with normal renal function who were used as a reference (p < 0.01). Other pharmacokinetic parameters such as maximum plasma drug concentration (Cmax)' biological half-life (th) and time to reach Cmax (!max) were not significantly different between the 2 groups. 24 hours after administration, the ACE inhibitions in haemodialysis patients were significantly higher than those in patients with normal renal function. There were no other significant differences between the 2 groups. The peak level of diacid (C max ) in haemodialysis patients on the nondialysis day was significantly greater than that on the dialysis day (p < 0.05). Other pharmacokinetic parameters such as AUC, th and !max were not significantly different between these 2 days. These parameters in the CAPD patient were similar to those in the haemodialysis patients on dialysis day. The results suggest that the elimination route of temocapril is mainly via the biliary route, but is partially a route permeated through a dialyser membrane or peritoneal membrane. It is suggested that temocapril is preferable to ACE inhibitors with renal elimination in the treatment of patients with hypertension undergoing dialysis.The number of dialysis patients has been increasing steadily each year, presenting a number of complications. Hypertension is important in determining the quality of life of dialysis patients. Consequently, many antihypertensive agents have been used in the treatment of dialysis patients with hypertension.Recently, a number of angiotensin converting
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