Pharmacokinetics of spirapril and spiraprilat in patients with chronic renal failure.
In this single-blind trial with a 2-week placebo run-in followed by a 4-week active-treatment period, patients were given 6 mg of spirapril once daily. Forty-nine hypertensive men and women were recruited; all had pretreatment diastolic blood pressures (DBP) of 95-115 mmHg with varying degrees of renal impairment. Regression analysis of pharmacokinetic parameters C(max)ss (the maximum steady-state drug concentration in plasma during a dosing interval), Cl/f (total plasma clearance) and k (elimination rate constant) of spirapril on creatinine clearance (Clcr) showed that the pharmacokinetics of spirapril were not significantly influenced by the degree of renal impairment. C(max)ss values of spiraprilat, however, increased with decreasing Clcr, and AUC(l)ss (area under the concentration-time curve during a dosing interval) values also increased. Regression analysis of the pharmacokinetic parameters C(max)ss, Clm/fm (total plasma clearance) and lambda 1 (rate constant of the first disposition phase) of spiraprilat on Clcr showed that Clm/fm as well as lambda 1 were linearly correlated with Clcr (p < 0.01). However, the results indicate that, even when renal elimination is completely blocked, there is significant elimination of spiraprilat through a non-renal pathway. In conclusion, the risk of drug accumulation after multiple dosing is minimal as the presence of a substantial non-renal spiraprilat elimination was consistently demonstrated.
Stein
G
G
Friedrich-Schiller University of Jena, Nephrology Department, Germany.
Sierakowski
B
B
Grass
P
P
Haufe
C C
CC
Jansa
U
U
Weidinger
G
G
D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics*; D003404:Creatinine / Q000378:metabolism; D004656:Enalapril / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012044:Regression Analysis; D016037:Single-Blind Method
D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril; C052555:spirapril; D003404:Creatinine; C076884:spiraprilat