Comparison of the Steady-State Pharmacokinetics of Fosinopril, Lisinopril and Enalapril in Patients with Chronic Renal Insufficiency

Abstract

The phosphinyl ester prodrug fosinopril, a new angiotensin converting enzyme (ACE) inhibitor, is fully hydrolysed after oral administration to the pharmacologically active diacid, fosinoprilat. This metabolite is cleared by both hepatic and renal routes, while most other ACE inhibitors are cleared exclusively by the kidney. In the present study, after administration of multiple fixed oral doses the accumulation of the active moieties of fosinopril, enalapril and lisinopril was compared in patients with renal insufficiency. 29 patients with creatinine clearances (CLCR) less than 30 ml/min received either fosinopril 10mg (n = 9), enalapril 2.5mg (n = 10) or lisinopril 5mg (n = 10) once daily for 10 days in a nonblind (open-label) parallel study. Pharmacokinetic parameters including area under the serum concentration-time curve (AUC), peak serum concentration (Cmax) and time to peak concentration (tmax), as well as renal function, blood pressure, and plasma renin activity (PRA) and aldosterone levels, were determined on the first and last days of the study. The percentage (+/- SEM) increases in AUC from day 1 to day 10 for fosinoprilat, enalaprilat and lisinopril were 26.8 +/- 9.9 (nonsignificant), 76.6 +/- 16.6 (p less than 0.001) and 161.7 +/- 31.8% (p less than 0.001), respectively. These results indicate that there was significantly less accumulation of fosinoprilat, based on accumulation indices, relative to either enalaprilat (p less than 0.05) or lisinopril (p less than 0.001) during the study. The Cmax of fosinopril increased significantly less than that of lisinopril (21.1 vs 123.6%; p less than 0.01). Renal function was not altered in any group, and blood pressure changed modestly.(ABSTRACT TRUNCATED AT 250 WORDS)

High serum enalaprilat in chronic renal failure

“…Clearance of enalaprilat was closely correlated with renal function, in all nine patients exceeding GFR (Figure 3). This has also been found in other studies, [32][33][34] and probably reflects the involvement of tubular secretion in the elimination of enalaprilat.…”

Fosinopril: Emerging Considerations and Implications for Angiotensin‐Converting Enzyme Inhibitor Therapy

“…The long-term dosing studies of Sica et al. (97,99) in patients with advanced renal failure (creatinine clearance <30 ml/min) further verify the importance of hepatic elimination to the maintenance of "clinically normal'' fosinoprilat kinetics in the renal failure population (Fig. 2) (99).…”

“…(97,99) in patients with advanced renal failure (creatinine clearance <30 ml/min) further verify the importance of hepatic elimination to the maintenance of "clinically normal'' fosinoprilat kinetics in the renal failure population (Fig. 2) (99). In these studies, once-daily administration for ten consecutive days of either fosinopril, enalapril, or lisinopril is accompanied by accumulation indices (AI) (AUCDay ,dAUC,,, ,) of 1.27, 1.77, and 2.62, respectively (99).…”

Fosinopril/hydrochlorothiazide: single dose and steady‐state pharmacokinetics and pharmacodynamics

“…Fosinoprilat differs from other currently available ACE Introduction inhibitors in two ways: (1) it is the only phosphinic acid ACE inhibitor; and (2) it is eliminated by a hepatic Fosinopril sodium is a prodrug of the angiotensinconverting-enzyme (ACE) inhibitor, fosinoprilat.…”

“…pathway in addition to the renal pathway shared by the other clinically available ACE inhibitors [1]. After oral administration, fosinopril is completely hydrolysed to renal impairment, total clearance of fosinopril was over-the-counter preparations, within 1 week of the first study-drug administration.…”