title: Comparison of the pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency.
abstract: OBJECTIVE
  To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril.
  
  
  METHODS
  Patients with congestive heart failure (CHF, NYHA Class II-IV) and chronic renal insufficiency (creatinine clearance </=30 ml min-1 ) were randomized to receive fosinopril, enalapril or lisinopril in two parallel-group studies. In the first study 24 patients were treated with 10 mg fosinopril (n=12 patients) or 2.5 mg enalapril (n=12) every morning for 10 consecutive days. In the second study 31 patients were treated with 10 mg fosinopril (n=16 patients) or 5 mg lisinopril (n=15) every morning for 10 consecutive days. Samples of blood were collected for determination of pharmacokinetic parameters. The area under the curve (AUC) between the first and last days of treatment and the accumulation index (AI) were the primary outcome measures.
  
  
  RESULTS
  All three angiotensin converting enzyme (ACE) inhibitors exhibited a significant increase in AUC between the first and last days of treatment in both studies. The difference between the AI for fosinoprilat (1.41) and enalaprilat (1.96) was statistically significant (95% CI: 1.05, 1.84). Similarly, the difference between the AI for fosinoprilat (1.21) and lisinopril (2.76) was statistically significant (95% CI: 1.85, 2.69). All three ACE inhibitors completely inhibited serum ACE for 24 h. All treatments were well tolerated.
  
  
  CONCLUSIONS
  Fosinoprilat exhibits significantly less accumulation than enalaprilat or lisinopril in patients with CHF and renal insufficiency, most probably because fosinoprilat is eliminated by both the kidney and liver, and increased hepatic elimination can compensate for reduced renal clearance in patients with kidney dysfunction.
authors.affiliation: Edgeware General Hospital, Edgeware, UK.
authors.forename: R
authors.initials: R
authors.lastname: Greenbaum
authors.forename: P
authors.initials: P
authors.lastname: Zucchelli
authors.forename: A
authors.initials: A
authors.lastname: Caspi
authors.forename: H
authors.initials: H
authors.lastname: Nouriel
authors.forename: R
authors.initials: R
authors.lastname: Paz
authors.forename: S
authors.initials: S
authors.lastname: Sclarovsky
authors.forename: P
authors.initials: P
authors.lastname: O'Grady
authors.forename: K F
authors.initials: KF
authors.lastname: Yee
authors.forename: W C
authors.initials: WC
authors.lastname: Liao
authors.forename: B
authors.initials: B
authors.lastname: Mangold
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D015773:Enalaprilat / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D017328:Fosinopril / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006333:Heart Failure / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D017706:Lisinopril / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D013997:Time Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A; D015773:Enalaprilat; D017328:Fosinopril; C046965:fosinoprilat