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High serum enalaprilat in chronic renal failure

Department of Nephrology and Clinical Physiology and Nuclear Medicine, Herlev Hospital, University of Copenhagen, thomaselungjensen{at}hotmail.com, Department of Clinical Pharmacology, Gentofte Hospital, University of Copenhagen

Jens Heisterberg

Department of Clinical Pharmacology, Gentofte Hospital, University of Copenhagen

Anne-Lise Kamper

Department of Nephrology and Clinical Physiology and Nuclear Medicine, Herlev Hospital, University of Copenhagen

Jesper Sonne

Department of Clinical Pharmacology, Gentofte Hospital, University of Copenhagen

Svend Strandgaard

Department of Nephrology and Clinical Physiology and Nuclear Medicine, Herlev Hospital, University of Copenhagen

Niels Erik Larsen

Laboratory of Clinical Pharmacology, Glostrup Hospital, University of Copenhagen, Denmark

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 µmol/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 m ². 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%.

Conclusion

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.

Key Words: Chronic renal failure • dosing guidelines • angiotensin-I-converting enzyme inhibitors • enalapril • enalaprilat • pharmacokinetics

Journal of Renin-Angiotensin-Aldosterone System, Vol. 2, No. 4, 240-245 (2001)
DOI: 10.3317/jraas.2001.038


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