This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Elung-Jensen, T. Articles by Larsen, N. E. Search for Related Content PubMed PubMed Citation Articles by Elung-Jensen, T. Articles by Larsen, N. E. Social Bookmarking                         What's this?

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

References

• The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157:2413-46.[Abstract/Free Full Text]
• Guidelines subcommittee. 1999 World Health Organization - International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens 1999;17(2):151-83.[Web of Science][Medline] [Order article via Infotrieve]
• Salvetti A., Mattei P., Sudano I. Renal Protection and Antihypertensive Drugs. Current Status. Drugs 1999;57:665-93.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Seyffart G. Drug Dosage in Renal Insufficiency, ed 1, Dordrecht, Kluwer Academic Publishers, 1991;218-9.
• Hoyer J., Schulte KL, Lenz T. Clinical pharmacokinetics of angiotensin converting enzyme (ACE) inhibitors in renal failure. Clin Pharmacokinet 1993;24:230-54.[Web of Science][Medline] [Order article via Infotrieve]
• GISEN: Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 1997;349:1857-63.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Hannedouche T., Landais P., Goldfarb B. et al. Randomised controlled trial of enalapril and beta blockers in non-diabetic chronic renal failure. BMJ 1994;309:833-7.[Abstract/Free Full Text]
• Ihle BU,Whitworth JA, Shahinfar S., CnaanA., Kincaid-Smith PS, Becker GJ Angiotensin-converting enzyme inhibition in nondiabetic progressive renal insufficiency: a controlled double-blind trial. Am J Kidney Dis 1996;27:489-95.[Web of Science][Medline] [Order article via Infotrieve]
• Kamper AL, Strandgaard S., Leyssac PP: Effect of enalapril on the progression of chronic renal failure.A randomized controlled trial. Am J Hypertens 1992;5:423-30.[Web of Science][Medline] [Order article via Infotrieve]
• Maschio G., Alberti D., Janin G. et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl JMed 1996;334:939-45.[Abstract/Free Full Text]
• Peters H., Ritz E. Dosing angiotensin II blockers--beyond blood pressure. Nephrol Dial Transplant 1999;14:2568-70.[Free Full Text]
• Kampmann J., Siersbaek-Nielsen K., Kristensen M., Hansen JM Rapid evaluation of creatinine clearance. Acta Med Scand 1974;196:517-20.[Web of Science][Medline] [Order article via Infotrieve]
• Brøchner-Mortensen J. A simple method for the determination of glomerular filtration rate. Scand J Clin Lab Invest 1972;30:271-4.[Web of Science][Medline] [Order article via Infotrieve]
• Lundberg P-A., Lindstedt G., Andersson T., Branegård B., Lundquister G., Nyström E. Single-Reagent Microcentrifugal Assay for Angiotensin Converting Enzyme in Serum. Clinical Chemistry 1984;30:163.[Free Full Text]
• Lindpaintner K., Pfeffer MA, Kreutz R. et al. A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med 1995;332:706-11.[Abstract/Free Full Text]
• Rowland M., Tozer TN Clinical Pharmacokinetics. Concepts and Applications, ed 3, Williams &Wilkins, 1995.
• Ulm EH, Hichens M., Gomez HJ et al. Enalapril maleate and a lysine analogue (MK-521): disposition in man. Br J Clin Pharmacol 1982;14:357-62.[Web of Science][Medline] [Order article via Infotrieve]
• Till AE, Gomez HJ, Hichens M. et al. Pharmacokinetics of repeated single oral doses of enalapril maleate (MK-421) in normal volunteers. Biopharm Drug Dispos 1984;5:273-80.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Churg J., Cotran RS, Sinniah R., Sakaguchi H., Sobin L. Renal Disease: classification and atlas of tubulo-interstitial diseases. Tokyo, Igaru-Shoin, 185.
• Anderson S., Meyer TW, Rennke HG, Brenner BM Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass. J Clin Invest 1985;76:612-19.[Web of Science][Medline] [Order article via Infotrieve]
• Lapinski R., Perico N., Remuzzi A., Sangalli F., Benigni A., Remuzzi G. Angiotensin II modulates glomerular capillary permselectivity in rat isolated perfused kidney. J Am Soc Nephrol 1996;7:653-60.[Abstract]
• Kamper AL, Holstein RN, Leyssac PP, Strandgaard S. The influence of angiotensin-converting enzyme inhibition on renal tubular function in progressive chronic nephropathy.Am J Kidney Dis 1996;28:822-31.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Higashi Y., Oshima T., Sasaki S. et al.Angiotensin-converting enzyme inhibition, but not calcium antagonism, improves a response of the renal vasculature to L-arginine in patients with essential hypertension. Hypertension 1998;32:16-24.[Abstract/Free Full Text]
• Wolf G., Haberstroh U., Neilson EG Angiotensin II stimulates the proliferation and biosynthesis of type I collagen in cultured murine mesangial cells.AmJPathol 1992;140:95-107.[Abstract]
• Wolf G., Ziyadeh FN The role of angiotensin II in diabetic nephropathy: emphasis on nonhemodynamic mechanisms. Am J Kidney Dis 1997;29:153-63.[Web of Science][Medline] [Order article via Infotrieve]
• MimranA, Ribstein J., DuCailar G. Contrasting effect of antihypertensive treatment on the renal response to L-arginine. Hypertension 1995;26:937-41.[Abstract/Free Full Text]
• Keilani T., Danesh FR, Schlueter WA, Molteni A., Batlle D. A subdepressor low dose of ramipril lowers urinary protein excretion without increasing plasma potassium. Am J Kidney Dis 1999;33:450-7.[Web of Science][Medline] [Order article via Infotrieve]
• Packer M., Poole-Wilson PA, Armstrong PW et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure.ATLAS Study Group. Circulation 1999;100:2312-8.[Abstract/Free Full Text]
• AjayiAA, Campbell BC, Kelman AW, Howie C., Meredith PA, Reid JL Pharmacodynamics and population pharmacokinetics of enalapril and lisinopril. Int J Clin Pharmacol Res 1985;5:419-27.[Web of Science][Medline] [Order article via Infotrieve]
• Weisser K., Schloos J., Lehmann K., Dusing R., Vetter H., Mutschler E. Pharmacokinetics and converting enzyme inhibition after morning and evening administration of oral enalapril to healthy subjects. Eur J Clin Pharmacol 1991;40:95-9.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Fruncillo RJ, Rocci-ML J., Vlasses PH et al. Disposition of enalapril and enalaprilat in renal insufficiency. Kidney Int Suppl 1987;20:S117-S122.[Medline] [Order article via Infotrieve]
• Mujais SK, QuintanillaA, Zahid M., Koch K., Shaw W., Gibson T. Renal handling of enalaprilat. Am J Kidney Dis 1992;19:121-5.[Web of Science][Medline] [Order article via Infotrieve]
• Lowenthal DT, Irvin JD, Merrill D. et al.The effect of renal function on enalapril kinetics. Clin Pharmacol Ther 1985;38:661-6.[Web of Science][Medline] [Order article via Infotrieve]
• Sica DA, Cutler RE, Parmer RJ, Ford NF Comparison of the steady-state pharmacokinetics of fosinopril, lisinopril and enalapril in patients with chronic renal insufficiency. Clin Pharmacokinet 1991;20:420-7.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Edeki T., Johnston A., Li-Kam WE, Turner P. Enalapril pharmacokinetics and ACE inhibition, following single and chronic oral dosing. Int J Clin Pharmacol Ther 1994;32:142-6.[Web of Science][Medline] [Order article via Infotrieve]
• Rigat B., Hubert C., Alhenc-Gelas F., Cambien F., Corvol P., Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343-6.[Web of Science][Medline] [Order article via Infotrieve]
• McLaughlin KJ, Harden PN, Ueda S., Boulton JJ, Connell JM, Jardine AGThe role of genetic polymorphisms of angiotensin-converting enzyme in the progression of renal diseases. Hypertension 1996;28:912-5.[Abstract/Free Full Text]
• Parving HH, Jacobsen P., Tarnow L. et al. Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme: observational follow up study. BMJ 1996;313:591-4.[Abstract/Free Full Text]
• Schmidt S., Strojek K., Grzeszczak W.,Bergis K., Ritz E. Excess of DD homozygotes in haemodialysed patients with type II diabetes. The Diabetic Nephropathy Study Group. Nephrol Dial Transplant 1997;12:427-9.[Abstract/Free Full Text]
• Jacobsen P., Rossing K., Rossing P. et al. Angiotensin converting enzyme gene polymorphism and ACE inhibition in diabetic nephropathy. Kidney Int 1998;53:1002-6.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Tarnow L., Parving HH, Jacobsen P. et al. The significance of deletion polymorphism in the ACE gene for progression of diabetic nephropathies treated with ACE inhibitors. Ugeskr Laeger 1998;160:4886-9.[Medline] [Order article via Infotrieve]
• van Essen G., Rensma PL, de Zeeuw D. et al. Association between angiotensin-converting-enzyme gene polymorphism and failure of renoprotective therapy. Lancet 1996;347:94-5.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

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


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				M. Frimodt-Moller, A. Hoj Nielsen, S. Strandgaard, and A.-L. Kamper Feasibility of combined treatment with enalapril and candesartan in advanced chronic kidney disease Nephrol. Dial. Transplant., November 9, 2009; (2009) gfp547v1. [Abstract] [Full Text] [PDF]

This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Elung-Jensen, T. Articles by Larsen, N. E. Search for Related Content PubMed PubMed Citation Articles by Elung-Jensen, T. Articles by Larsen, N. E. Social Bookmarking                         What's this?