PHARMACOKINETICS AND ACUTE EFFECT ON THE RENINANGIOTENSIN SYSTEM OF DELAPRIL IN PATIENTS WITH CHRONIC-RENAL-FAILURE

  • 1 February 1987
    • journal article
    • research article
    • Vol. 27  (2) , 65-70
Abstract
The acute effect on the renin-angiotensin system and the pharmacokinetic properties of delapril, a new angiotensin converting enzyme inhibitor and its active diacid metabolites (delapril diacid and 5-hydroxy delapril diacid) arising from delapril in vivo were investigated in 4 hypertensive patients with chronic renal failure (CRF: 4 males, average age 49.5 (37-64) years, mean Ccr 22.2 ml/min/1.73 m3) and 9 patients with essential hypertension (EH: 6 males, 3 females, average age 42.8 (28-61) years, mean Ccr 79.3 ml/min/1.73 m2). In CRF, following a single dose of delapril hydrochloride (30 mg), the biological half lives (t1/2) of delapril diacid and 5-OH-delapril diacid were 4.69, 12.88 hours, the maximum serum concentration (Cmax) and the area under the plasma concentration-time curve ([AUC]024) of delapril and its diacid metabolites were 414, 797 and 435 ng/ml, and 658, 6400 and 5068 ng .cntdot. H/ml, respectively. In EH, the t1/2 of delapril diacid and 5-OH-delapril diacid were 1.21, 1.40 hours and the Cmax and [AUC]024 of delapril and its diacid metabolites were 489, 635 and 229 ng/ml, and 572, 1859 and 948 ng .cntdot. h/ml, respectively. The [AUC]024 in CRF were significantly increased as compared with those in EH. The cumulative urinary excretions were significantly lower in CRF than in EH. The serum angiotensin converting enzyme (ACE) was markedly inhibited in both groups up to 24 hours. The plasma concentration of angiotensin II decreased in both groups. Significant positive correlations were found in the diacid metabolites between the inverse of creatinine clearance and [AUC]024 (delapril diacid: r = 0.983, p < 0.01, [AUC]024 = 130,522 .times. 1/Ccr - 6.7 and 5-OH-delapril diacid: r = 0.949, p < 0.01, [AUC]024 = 100,932 .times. 1/Ccr - 383). These results indicate that delapril may represent a useful antihypertensive agent in both EH and CRF, and suggest that patients with impaired renal function may be given smaller doses than the usual dose of delapril.