Long-Term Plasma Levels and Dose Modulation of Alacepril in Patients with Chronic Renal Failure

Abstract

Because most angiotensin-converting enzyme inhibitors are excreted into urine, any decrease in renal function increases the plasma levels of these drugs. This study was designed to investigate the appropriate doses of alacepril in patients with chronic renal failure. The total plasma concentration of captopril, an active metabolite of alacepril, was measured in 47 patients with chronic renal failure or normal renal function. Fifteen patients on chronic hemodialysis were also enrolled in this study. In patients treated with 12.5, 25 and 50 mg alacepril, the plasma concentration of captopril was linearly correlated with serum creatinine and creatinine clearance (Ccr). There was an approximately 40% decrease of the plasma captopril concentration after 4 h of hemodialysis. Among patients treated with 25 or 50 mg alacepril for 4.5 years, the plasma concentration of captopril gradually increased along with an increase in serum creatinine (from 2.0 to 5.8, and from 1.9 to 7.1 mg/dL, respectively). Although the plasma concentration of captopril was higher in the 50 mg group, the increase in serum creatinine during this period was not different between the two groups. The plasma aldosterone concentration did not increase during this period. These data suggest that alacepril should be reduced from 50 to 25 and 12.5 mg/day in patients with a serum creatinine level of greater than 2−3 and 4−6 mg/dL, respectively, in order to maintain a plasma level equivalent to that in subjects with normal renal function receiving 50 mg/day alacepril. For patients on chronic hemodialysis, 12.5 mg alacepril is the appropriate dose. (Hypertens Res 2008; 31: 29−36)

References

  1. 1

    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: 612–619.

    CAS  Article  Google Scholar 

  2. 2

    Remuzzi A, Puntorieri S, Battaglia C, Bertani T, Remuzzi G : Angiotensin converting enzyme inhibition ameliorates glomerular filtration of macromolecules and water and lessens glomerular injury in the rat. J Clin Invest 1990; 85: 541–549.

    CAS  Article  Google Scholar 

  3. 3

    Makino H, Nakamura Y, Wada J : Remission and regression of diabetic nephropathy. Hypertens Res 2003; 26: 515–519.

    Article  Google Scholar 

  4. 4

    The Groppo Italiano Studi Epidemilogici in Nefrologia (GISEN) : Randomized placebo controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997; 349: 1857–1863.

  5. 5

    Ruggenenti P, Perna A, Gherardi G, et al : Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999; 354: 359–364.

    CAS  Article  Google Scholar 

  6. 6

    Chiurchiu C, Remuzzi G, Ruggenenti P : Angiotensin-converting enzyme inhibition and renal protection in nondiabetic patients: the data of the meta-analyses. J Am Soc Nephrol 2005; 16 ( Suppl 1): S58–S63.

    CAS  Article  Google Scholar 

  7. 7

    Pillans PI, Landsberg PG, Fleming AM, Fanning M, Sturtevant JM : Evaluation of dosage adjustment in patients with renal failure. Int Med J 2003; 33: 10–13.

    CAS  Article  Google Scholar 

  8. 8

    Elung-Jensen T, Heisterberg J, Kamper AL, Sonne J, Strandgaard S : Blood pressure response to conventional and low-dose enalapril in chronic renal failure. Br J Clin Pharmacol 2003; 55: 139–146.

    CAS  Article  Google Scholar 

  9. 9

    Navis G, Kramer AB, de Jong PE : High-dose ACE inhibition: can it improve renoprotection? Am J Kidney Dis 2002; 40: 664–666.

    Article  Google Scholar 

  10. 10

    Sakamaki Y, Sasamura H, Ikeda S, Ikegami N, Saruta T : Comparison of health costs associated with treatment of hypertension with a calcium channel blocker and angiotensin-converting enzyme inhibitor in the United States and Japan. Hypertens Res 2006; 29: 333–338.

    Article  Google Scholar 

  11. 11

    Ahuja TS, Freeman D Jr, Mahnken JD, Agraharkar M, Siddiqui M, Memon A : Predictors of the development of hyperkalemia in patients using angiotensin-converting enzyme inhibitors. Am J Nephrol 2000; 20: 268–272.

    CAS  Article  Google Scholar 

  12. 12

    Chobanian AV, Bakris GL, Black HR, et al, National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee : The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560–2572.

    CAS  Article  Google Scholar 

  13. 13

    MacFadyen RJ, Struthers AD : The practical assessment of compliance with ACE-inhibitor therapy—a novel approach. J Cardiovasc Pharmacol 1997; 29: 119–124.

    CAS  Google Scholar 

  14. 14

    Brunner-La Rocca HP, Weilenmann D, Kiowski W, Maly FE : Plasma levels of enalaprilat in chronic therapy of heart failure: relationship to adverse events. J Pharmacol Exp Ther 1999; 289: 565–571.

    CAS  PubMed  Google Scholar 

  15. 15

    Kelly JG, Doyle GD, Carmody M, Glover DR, Cooper MD : Pharmacokinetics of lisinopril, enalapril and enalaprilat in renal failure; effects of haemodialysis. Br J Clin Pharmacol 1988; 26: 781–786.

    CAS  Article  Google Scholar 

  16. 16

    Greenbaum R, Zucchelli P, Caspi A, et al : Comparison of pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency. Br J Clin Pharmacol 2000; 49: 23–31.

    CAS  Article  Google Scholar 

  17. 17

    Johnston CI, Jackson B, McGrath B, Matthews G, Arnolda L : Relationship of antihypertensive effect of enalapril to serum MK-442 levels and angiotensin converting enzyme inhibition. J Hypertens 1983; 1 ( Suppl): 71–75.

    CAS  Google Scholar 

  18. 18

    Takeyama K, Minato H, Ikeno A, Hosoki K, Kadokawa T : Antihypertensive mechanism of alacepril: effect on norepinephrine-induced vasoconstrictive response in vitro and in vivo. Arzneimittelforschung 1986; 36: 74–77.

    CAS  PubMed  Google Scholar 

  19. 19

    Matsumoto K, Miyazaki H, Fujii T, Yoshida K, Amejima H, Hashimoto M : Disposition and metabolism of the novel antihypertensive agent alacepril in rats. Arzneimittelforschung 1986; 36: 40–46.

    CAS  PubMed  Google Scholar 

  20. 20

    Matsumoto K, Nambu K, Fujii T, Takeyama K, Miyazaki H, Hashimoto M : Metabolism of protein conjugate of desacetyl-alacepril and its effect on angiotensin converting enzyme in renal hypertensive rats. Arzneimittelforschung 1986; 36: 52–54.

    CAS  PubMed  Google Scholar 

  21. 21

    Lee AF, MacFadyen RJ, Struthers AD : Neurohormonal reactivation in heart failure patients on chronic ACE inhibitor therapy: a longitudinal study. Eur J Heart Fail 1999; 1: 401–406.

    CAS  Article  Google Scholar 

  22. 22

    Cockcroft DW, Gault MH : Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41.

    CAS  Article  Google Scholar 

  23. 23

    van Essen GG, Rensma PL, de Zeeuw D, et al : Association between angiotensin-converting-enzyme gene polymorphism and failure of renoprotective therapy. Lancet 1996; 347: 94–95.

    CAS  Article  Google Scholar 

  24. 24

    Nonoguchi H, Kiyama S, Inoue H, et al : Angiotensin-converting enzyme inhibitor withdrawal and ACE gene polymorphism. Clin Nephrol 2003; 60: 225–232.

    CAS  Article  Google Scholar 

  25. 25

    Hayashi K, Miyamoto M, Sekine Y : Determination of captopril and its mixed disulphides in plasma and urine by high-performance liquid chromatography. J Chromatogr 1985; 338: 161–169.

    CAS  Article  Google Scholar 

  26. 26

    Onoyama K, Hirakata H, Tsuruda H, et al : Pharmacokinetics of a new angiotensin I converting enzyme inhibitor (alacepril) after oral dosing in fasting or fed states. Clin Pharmacol Ther 1985; 38: 462–468.

    CAS  Article  Google Scholar 

  27. 27

    Tomita K, Nooguchi H, Terda Y, Marumo F : Renal effects of alacepril in essential hypertension. J Cardiovasc Pharmacol 1992; 20: 520–524.

    CAS  Article  Google Scholar 

  28. 28

    Onoyama K, Kumagaya H, Nanishi F, et al : Drug movement of alacepril, an angiotensin-converting enzyme inhibitor in subjects with reduced renal function. Kiso to Rinsho 1985; 19: 479–486 ( in Japanese).

    Google Scholar 

  29. 29

    van der Kleij FGH, de Jong PE, Henning RH, et al : Enhanced responses of blood pressure, renal function, and aldosterone to angiotensin I in the DD genotype are blunted by low sodium intake. J Am Soc Nephrol 2002; 13: 1025–1033.

    CAS  PubMed  Google Scholar 

  30. 30

    Danilczyk U, Penninger JM : Angiotensin-converting enzyme II in the heart and the kidney. Circ Res 2006; 98: 463–471.

    CAS  Article  Google Scholar 

  31. 31

    Sato A, Suzuki Y, Shibata H, Saruta T : 2000. Plasma aldosterone concentrations are not related to the degree of angiotensin-converting enzyme inhibition in essential hypertensive patients. Hypertens Res 2000; 23: 25–31.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Hiroshi Nonoguchi.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nonoguchi, H., Kiyama, S., Kitamura, K. et al. Long-Term Plasma Levels and Dose Modulation of Alacepril in Patients with Chronic Renal Failure. Hypertens Res 31, 29–36 (2008). https://doi.org/10.1291/hypres.31.29

Download citation

Keywords

  • angiotensin-converting enzyme inhibitor
  • chronic renal failure
  • dose modulation
  • hypertension

Further reading

Search