Pharmacokinetics and pharmacodynamics of quinaprilat after low dose quinapril in patients with terminal renal failure

Abstract

The pharmacokinetics and pharmacodynamics of the ACE inhibitor quinaprilat have been studied in six chronic haemodialysis (HD) patients and in six patients undergoing continuous ambulatory peritoneal dialysis (CAPD) after a single oral dose of 2.5 mg quinapril. Mean tmax and Cmax values (SEM) for quinaprilat in interdialytic HD patients were 4.0 (0) h and 84 (8.4) ng.ml-1 respectively, and they did not differ significantly from those in CAPD patients (4.7 (0.7) h and 64 (5.7) ng.ml-1). Elimination half lives were 30 (10.1) h (HD) and 34 (7.3) h (CAPD). Cmax, tmax, t1/2, and AUC were increased and CL was decreased compared to data reported previously after giving 2.5 mg to healthy subjects. Peritoneal clearance was calculated as 0.1 (0.1) ml.min-1, thus less than 0.5% of the dose were removed within 24 h by CAPD. ACE activity was suppressed by more than 93% between 4 and 24 h postdose (P < 0.001). It decreased in both groups with increasing plasma quinaprilat levels. Angiotensin II concentration compared to baseline was significantly decreased at 4 hours (-30.4 +/- 10%) and 24 h (-30 +/- 9.9%) (P < 0.05, n = 11), while active plasma renin concentration was still significantly increased at 48 h postdose (+ 60.2 +/- 14.5%, P < 0.01). Mean arterial pressure 24 h postdose was significantly (P < 0.05) decreased in HD (-12 mmHg) and CAPD patients (-20 mm Hg). Only two patients reported unwanted effects (fatigue, dizziness, nausea, and weakness). In conclusion, due to its long lasting effect on ACE activity and on blood pressure in terminal renal failure a starting dose of quinapril 2.5 mg o.d. may be used in hypertensive HD and CAPD patients.

Elimination Kinetics of Quinaprilat and Perindoprilat in Hypertensive Patients with Renal Failure on Haemodialysis

“…It has been reported that the pharmacokinetics of these parent drugs are not influenced by renal failure. 8,18,20) Contrary to the parent drugs, the pharmacokinetics of their metabolites would be differentially influenced by renal failure 1,4,15,21) since the percentages of urinary recovery of quinaprilat and perindoprilat in normal subjects are different (quinaprilat: approximately 30%; perindoprilat: approximately 15%). 8,15) It is well known that renal failure causes the accumulation of various endogenous and exogenous substances in the body and that haemodialyzability of such substances in plasma is affected by various factors, such as molecular weight, hydrophobicity, protein binding potency and volume of distribution.…”

“…Quinaprilat has a high hydrophobicity and binds extensively to plasma proteins (97%) 8) although the volume of distribution is relatively small (0.3 l/kg). 21) On the other hand, it has been reported that the protein binding of perindopril in patients with renal failure is approximately 75% whereas that of its active metabolite, perindoprilat, is approximately 20%. 5,22) On the basis of these findings, the low haemodialyzability of quinaprilat may be due to its hydrophobic property and high protein binding potency.…”