Clinical Pharmacokinetics

, Volume 20, Issue 5, pp 420–427

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

  • Domenic A. Sica
  • Ralph E. Cutler
  • Robert J. Parmer
  • Neville F. Ford
Original Research Article

DOI: 10.2165/00003088-199120050-00006

Cite this article as:
Sica, D.A., Cutler, R.E., Parmer, R.J. et al. Clin. Pharmacokinet. (1991) 20: 420. doi:10.2165/00003088-199120050-00006

Summary

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 < 0.001) and 161.7 ± 31.8% (p < 0.001), respectively. These results indicate that there was significantly less accumulation of fosinoprilat, based on accumulation indices, relative to either enalaprilat (p < 0.05) or lisinopril (p < 0.001) during the study. The Cmax of fosinopril increased significantly less than that of lisinopril (21.1 vs 123.6%; p < 0.01). Renal function was not altered in any group, and blood pressure changed modestly. PRA increased and plasma aldosterone decreased slightly after administration of each drug, although PRA in the fosinopril group was twice that in the other 2 groups. The results suggest that the nonrenal route of elimination of fosinoprilat helps minimise its accumulation in patients with renal insufficiency, and the minimal accumulation may reduce the risk of concentration-related adverse events.

Copyright information

© Adis International Limited 1991

Authors and Affiliations

  • Domenic A. Sica
    • 1
    • 2
    • 3
    • 4
  • Ralph E. Cutler
    • 1
    • 2
    • 3
    • 4
  • Robert J. Parmer
    • 1
    • 2
    • 3
    • 4
  • Neville F. Ford
    • 1
    • 2
    • 3
    • 4
  1. 1.Division of NephrologyMedical College of VirginiaRichmondUSA
  2. 2.Department of MedicineLoma Linda Veterans HospitalLoma LindaUSA
  3. 3.Division of Nephrology-HypertensionVeterans Administration Medical CenterSan DiegoUSA
  4. 4.Human Pharmacology, Worldwide Clinical Research and DevelopmentBristol-Myers Squibb Pharmaceutical Research InstitutePrincetonUSA

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