title: High serum enalaprilat in chronic renal failure.
abstract: BACKGROUND
  Most angiotensin-converting enzyme (ACE) inhibitors and their metabolites are excreted renally and doses should hence be reduced in renal insufficiency. We studied whether the dosage of enalapril in daily clinical practice is associated with drug accumulation of enalaprilat in chronic renal failure.
  
  
  METHODS
  Fifty nine out-patients with plasma creatinine >150 micromol/L and chronic antihypertensive treatment with enalapril were investigated, in a cross-sectional design.
  
  
  RESULTS
  Median glomerular filtration rate (GFR) was 23(range 6-60) ml/minute/1.73 m2. The daily dose of enalapril was 10 (2.5-20) mg and the trough serum concentration of enalaprilat was 31.8 (<2.5-584.7)ng/ml. Ninety percent of the patients had higher serum concentrations of enalaprilat than has been reported in subjects with normal kidney function, and a marked elevation of serum enalaprilat was observed in patients with GFR <30 ml/minute. All but three patients had serum ACE activity below the reference range. The ACE genotype did not influence the results. Additional pharmacokinetic studies were done in nine patients in whom GFR was 23 (10-42)ml/minute/1.73 m2. The median clearance of enalaprilat was 28 (16-68) ml/minute and correlated linearly with GFR (r=0.86, p=0.003). Intra-subject day-to-day variation in trough concentrations was 19.7%.
  
  
  CONCLUSIONS
  Patients with chronic renal failure given small or moderately high doses of enalapril may thus have markedly elevated levels of serum enalaprilat. Whether this affords extra renoprotection, or on the contrary may inappropriately impair renal function, is not known, and should be investigated in prospective, controlled studies.
authors.affiliation: Department of Nephrology, Herlev Hospital, Copenhagen, Denmark. thomaselungjensen@hotmail.com
authors.forename: T
authors.initials: T
authors.lastname: Elung-Jensen
authors.forename: J
authors.initials: J
authors.lastname: Heisterberg
authors.forename: A L
authors.initials: AL
authors.lastname: Kamper
authors.forename: J
authors.initials: J
authors.lastname: Sonne
authors.forename: S
authors.initials: S
authors.lastname: Strandgaard
authors.forename: N E
authors.initials: NE
authors.lastname: Larsen
mesh_terms: D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D003430:Cross-Sectional Studies; D004656:Enalapril / Q000008:administration & dosage / Q000097:blood; D015773:Enalaprilat / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate; D006801:Humans; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000235:genetics; D011110:Polymorphism, Genetic
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril; D007703:Peptidyl-Dipeptidase A; D015773:Enalaprilat