Clinical Pharmacokinetics

, Volume 41, Issue 3, pp 207–224 | Cite as

Clinical Pharmacokinetics and Selective Pharmacodynamics of New Angiotensin Converting Enzyme Inhibitors

An Update
Review Articles Drug Disposition


The angiotensin converting enzyme (ACE) inhibitors are widely used in the management of essential hypertension, stable chronic heart failure, myocardial infarction (MI) and diabetic nephropathy. There is an increasing number of new agents to add to the nine ACE inhibitors (benazepril, cilazapril, delapril, fosinopril, lisinopril, pentopril, perindopril, quinapril and ramipril) reviewed in this journal in 1990. The pharmacokinetic properties of five newer ACE inhibitors (trandolapril, moexipril, spirapril, temocapril and imidapril) are reviewed in this update.

All of these new agents are characterised by having a carboxyl functional groups and requiring hepatic activation to form pharmacologically active metabolites. They achieve peak plasma concentrations at similar times (tmax) to those of established agents. Three of these agents (trandolapril, moexipril and imidapril) require dosage reductions in patients with renal impairment. Dosage reductions of moexipril and temocapril are recommended for elderly patients, and dosages of moexipril should be lower in patients who are hepatically impaired. Moexipril should be taken 1 hour before meals, whereas other ACE inhibitors can be taken without regard to meals.

The pharmacokinetics of warfarin are not altered by concomitant administration with trandolapril or moexipril. Although imidapril and spirapril have no effect on digoxin pharmacokinetics, the area under the concentration-time curve of imidapril and the peak plasma concentration of the active metabolite imidaprilat are decreased when imidapril is given together with digoxin.

Although six ACE inhibitors (captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril) have been approved for use in heart failure by the US Food and Drug Administration, an overview of 32 clinical trials of ACE inhibitors in heart failure showed that no significant heterogeneity in mortality was found among enalapril, ramipril, quinapril, captopril, lisinopril, benazepril, perindopril and cilazapril. Initiation of therapy with captopril, ramipril, and trandolapril at least 3 days after an acute MI resulted in all-cause mortality risk reductions of 18 to 27%. Captopril has been shown to have similar morbidity and mortality benefits to those of diuretics and β-blockers in hypertensive patients. Captopril has been shown to delay the progression of diabetic nephropathy, and enalapril and lisinopril prevent the development of nephropathy in normoalbuminuric patients with diabetes.

ACE inhibitors are generally characterised by flat dose-response curves. Lisinopril is the only ACE inhibitor that exhibits a linear dose-response curve. Despite the fact that most ACE inhibitors are recommended for once-daily administration, only fosinopril, ramipril, and trandolapril have trough-to-peak effect ratios in excess of 50%.


  1. 1.
    Kelly JG, O’Malley K. Clinical pharmacokinetics of the newer ACE inhibitors: a review. Clin Pharmacokinet 1990; 19: 177–96PubMedCrossRefGoogle Scholar
  2. 2.
    Kubo SH, Cody RJ. Clinical pharmacokinetics of the angiotensin converting enzyme inhibitors: a review. Clin Pharmacokinet 1985; 10: 377–91PubMedCrossRefGoogle Scholar
  3. 3.
    Kaiser G, Ackermann R, Brechbuhler S, et al. Pharmacokinetics of the angiotensin-converting enzyme inhibitor, benazepril HCl (CGS 14824A), in healthy volunteers after single and repeated administration. Biopharm Drug Dispos 1989; 10: 365–76PubMedCrossRefGoogle Scholar
  4. 4.
    Dieterle W, Ackermann R, Kaiser G. Pharmacokinetics of benazeprilat after intravenous administration in healthy volunteers [abstract]. Eur J Clin Pharmacol 1989; 9 Suppl.: A303Google Scholar
  5. 5.
    Williams PEO, Brown AN, Rajaguru S, et al. The pharmacokinetics and bioavailability of cilazapril in normal man. Br J Clin Pharmacol 1989; 27: 181S–8SPubMedCrossRefGoogle Scholar
  6. 6.
    Shionoiri H, Yasuda G, Ikeda A, et al. Pharmacokinetics and depressor effect of delapril in patients with essential hypertension. Clin Pharmacol Ther 1987; 41: 74–9PubMedCrossRefGoogle Scholar
  7. 7.
    Onoyama K, Nanishi F, Okuda S, et al. Pharmacokinetics of a new angiotensin converting enzyme inhibitor (delapril) in patients with deteriorated kidney function and in normal control subjects. Clin Pharmacol Ther 1988; 43: 242–9PubMedCrossRefGoogle Scholar
  8. 8.
    Singhvi SM, Duchin KL, Morrison RA, et al. Disposition of fosinopril sodium in healthy subjects. Br J Clin Pharmacol 1988; 25: 9–15PubMedCrossRefGoogle Scholar
  9. 9.
    Ulm EH, Hichens M, Gomez HJ, et al. Enalapril maleate and a lysine analogue (MK521): disposition in man. Br J Clin Pharmacol 1982; 14: 357–62PubMedCrossRefGoogle Scholar
  10. 10.
    Rakhit A, Hurley ME, Tipnis V, et al. Pharmacokinetics and pharmacodynamics of pentopril, a new angiotensin-converting-enzyme inhibitor in humans. J Clin Pharmacol 1986; 26: 156–64PubMedGoogle Scholar
  11. 11.
    Rakhit A, Kochak GM, Tipnis V, et al. Pharmacokinetics of pentopril in the elderly. Br J Clin Pharmacol 1987; 24: 351–7PubMedCrossRefGoogle Scholar
  12. 12.
    Kochak GM, Rakhit A, Thompson TN, et al. Pentopril-cimetidine interaction caused by a reduction in hepatic blood flow. J Clin Pharmacol 1989; 28: 222–7Google Scholar
  13. 13.
    Rakhit A, Radensky P, Szerlip HM, et al. Effect of renal impairment on disposition of pentopril and its active metabolite. Clin Pharmacol Ther 1988; 44: 39–48PubMedCrossRefGoogle Scholar
  14. 14.
    Lees KR, Green ST, Reid JL. Influence of age on pharmacokinetics and pharmacodynamics of perindopril. Clin Pharmacol Ther 1988; 44: 418–25PubMedCrossRefGoogle Scholar
  15. 15.
    Ferry JJ, Cetnarowski AB, Sedman AJ, et al. Multiple dose cimetidine administration does not influence the single-dose pharmacokinetics of quinapril and its active metabolite (CI-928). J Clin Pharmacol 1988; 28: 48–51PubMedGoogle Scholar
  16. 16.
    Neub M, Vollmer K, Anderson J, et al. Pharmacokinetics of the ACE-inhibitor quinapril in young and elderly volunteers [abstract]. Eur J Clin Pharmacol 1989; 36 Suppl.: A222Google Scholar
  17. 17.
    Eckert HG, Badian MJ, Gantz D, et al. Pharmacokinetics and biotransformation of 2-(N-((S)-1-ethoxycarboxyl-3-phenylpropyl)-L-alanyl)-(1S, 3S, 5S)-2-azabicyclo (3.3.0) octane-3-carboxylic acid (Hoe 498) in rat, dog, and man. Arzneimittelforschung 1984; 34: 1435–47PubMedGoogle Scholar
  18. 18.
    Witte PU, Irmisch R, Hajdu P, et al. Pharmacokinetics and pharmacodynamics of a novel orally active angiotensin converting enzyme inhibitor (Hoe 498) in healthy subjects. Eur J Clin Pharmacol 1984; 27: 577–81PubMedCrossRefGoogle Scholar
  19. 19.
    Thuillez C, Richer C, Giudicelli JF. Pharmacokinetics, converting enzyme inhibition and peripheral arterial haemodynamics of ramipril in healthy volunteers. Am J Cardiol 1987; 59: 38D–44DPubMedCrossRefGoogle Scholar
  20. 20.
    Meyer BH, Muller O, Badian M, et al. Pharmacokinetics of ramipril in the elderly. Am J Cardiol 1987; 59: 33D–7DPubMedCrossRefGoogle Scholar
  21. 21.
    The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316: 1429–35CrossRefGoogle Scholar
  22. 22.
    Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303–10PubMedCrossRefGoogle Scholar
  23. 23.
    The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293–302CrossRefGoogle Scholar
  24. 24.
    Garg G, Yusuf S, Collaborative Group on ACE Inhibitor Trials. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995; 273: 1450–6PubMedCrossRefGoogle Scholar
  25. 25.
    Hobbs RE. Results of the ATLAS Study. High or low doses of ACE inhibitors for heart failure? Cleve Clin J Med 1998; 65: 539–42PubMedGoogle Scholar
  26. 26.
    Gruppo Italiano per lo Studio della Sopravvivenza nell’infarcto Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet 1994; 343: 1115–22Google Scholar
  27. 27.
    The Fourth International Study of Infarct Survival (ISIS-4) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet 1995; 345: 669–85CrossRefGoogle Scholar
  28. 28.
    Chinese Cardiac Study Collaborative Group. Oral captopril versus placebo among 13 634 patients with suspected acute myocardial infarction: interim report from the Chinese Cardiac Study (CCS-1). Lancet 1995; 345: 686–7CrossRefGoogle Scholar
  29. 29.
    Swedberg K, Held P, Kjekshus J, et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med 1992; 327: 678–84PubMedCrossRefGoogle Scholar
  30. 30.
    ACE Inhibitor Myocardial Infarction Collaborative Group. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. Circulation 1998; 97: 2202–12CrossRefGoogle Scholar
  31. 31.
    Pfeffer MA, Braunwald E, Moye LA, et al., for the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement trial. N Engl J Med 1992; 327: 669–77PubMedCrossRefGoogle Scholar
  32. 32.
    The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993; 342: 821–8Google Scholar
  33. 33.
    Kober L, Torp-Pedersen C, Carlsen JE, et al., Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995; 333: 1670–6PubMedCrossRefGoogle Scholar
  34. 34.
    Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329: 1456–62PubMedCrossRefGoogle Scholar
  35. 35.
    Marre M, Chatellier G, Leblanc H, et al. Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria. BMJ 1988; 297: 1092–5PubMedCrossRefGoogle Scholar
  36. 36.
    The EUCLID Study Group. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 1997; 349: 1787–92CrossRefGoogle Scholar
  37. 37.
    Ravid M, Savin H, Jurtin I, et al. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 1993; 118: 577–81PubMedGoogle Scholar
  38. 38.
    Rose M, McMahon FG. Some problems with antihypertensive drug studies in the context of the new guidelines. Am J Hypertens 1990; 3: 151–5PubMedGoogle Scholar
  39. 39.
    Goa KL, Wagstaff AJ. Losartan potassium: a review of its pharmacology, clinical efficacy, and tolerability in the management of hypertension. Drugs 1996; 51: 820–45PubMedCrossRefGoogle Scholar
  40. 40.
    Ellis ML, Patterson JH. A new class of antihypertensive therapy: angiotensin II antagonists. Pharmacotherapy 1996; 16: 849–60PubMedGoogle Scholar
  41. 41.
    Reid IA. Vasoactive peptides. In: Katzung BG, editor. Basic and clinical pharmacology. 7th ed. Stamford (CT): Appleton and Lange, 1998: 287–91Google Scholar
  42. 42.
    White CM. Pharmacologic, pharmacokinetic, and therapeutic differences among ACE inhibitors. Pharmacotherapy 1998; 18: 588–99PubMedGoogle Scholar
  43. 43.
    Edling O, Bao G, Feelisch M, et al. Moexipril, a new angiotensin-converting enzyme (ACE) inhibitor: pharmacological characterization and comparison with enalapril. J Pharmacol Exp Ther 1995; 275: 854–63PubMedGoogle Scholar
  44. 44.
    Chevillard C, Brown NL, Mathieu MN, et al. Differential effects of oral trandolapril and enalapril on rat tissue angiotensin converting enzyme. Eur J Pharmacol 1988; 147: 23–8PubMedCrossRefGoogle Scholar
  45. 45.
    Pinto YM, van Veldhuisen DJ, Tjon-Ka-Jie RT, et al. Dose-finding study of imidapril, a novel angiotensin converting enzyme inhibitor, in patients with stable chronic heart failure. Eur J Clin Pharmacol 1996; 50: 265–8PubMedCrossRefGoogle Scholar
  46. 46.
    Delacretaz E, Nussberger J, Puchler K, et al. Value of different clinical and biochemical correlates to assess angiotensin converting enzyme inhibition. J Cardiovasc Pharmacol 1994; 24: 479–85PubMedCrossRefGoogle Scholar
  47. 47.
    Unger TH, Gohlke P, Paul M, et al. Tissue renin-angiotensin-systems: fact or fiction? J Cardiovasc Pharmacol 1991; 18 Suppl. 2: 20–5Google Scholar
  48. 48.
    Hoogkamer JF, Kleinbloesem CH, Nokhodian A, et al. Pharmacokinetics of imidapril and its active metabolite imidaprilat following single dose and during steady state in patients with chronic renal failure. Eur J Clin Pharmacol 1998; 54: 59–61PubMedCrossRefGoogle Scholar
  49. 49.
    Delacretaz E, Nussberger J, Puchler K, et al. Value of different clinical and biochemical correlates to assess angiotensin converting enzyme inhibition. J Cardiovasc Pharmacol 1994; 24(3): 479–85PubMedCrossRefGoogle Scholar
  50. 50.
    Bardelay C, Mach E, Worcel M, et al. Angiotensin-converting enzyme in rat brain and extraneural tissues visualized by quantitative autoradiography using 3H-trandolaprilate. J Cardiovasc Pharmacol 1989; 14: 511–8PubMedCrossRefGoogle Scholar
  51. 51.
    Sybertz EJ, Watkins RW, Ahn HS, et al. Pharmacologic, metabolic, and toxicologic profile of spirapril (SCH 33844), a new angiotensin converting inhibitor. J Cardiovasc Pharmacol 1987; 10 Suppl. 7: S105–8PubMedCrossRefGoogle Scholar
  52. 52.
    Friehe H, Ney P. Pharmacological and toxicological studies of the new angiotensin converting enzyme inhibitor moexipril hydrochloride. Arzneimittelforschung 1997; 47(2): 132–44PubMedGoogle Scholar
  53. 53.
    Wiseman LR, McTavish D. Trandolapril: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in essential hypertension. Drugs 1994; 48: 71–90PubMedCrossRefGoogle Scholar
  54. 54.
    Arner P, Wade A, Engfeldt P, et al. Pharmacokinetics and pharmacodynamics of trandolapril after repeated administration of 2mg to young and elderly patients with mild-to-moderate hypertension. J Cardiovasc Pharmacol 1994; 23 Suppl. 4: S44–9PubMedGoogle Scholar
  55. 55.
    Brown NL, Batel M-Y, Benzoni F, et al. Angiotensin-converting enzyme inhibition, anti-hypertensive activity and hemodynamic profile of trandolapril (RU 44570). Eur J Pharmacol 1988; 148: 79–91PubMedCrossRefGoogle Scholar
  56. 56.
    Lenfant B, Mouren M, Bryce T, et al. Trandolapril: pharmacokinetics of single oral doses in healthy male volunteers. J Cardiovasc Pharmacol 1994; 23 Suppl. 4: S38–43PubMedGoogle Scholar
  57. 57.
    Danielson B, Querin S, LaRochelle P, et al. Pharmacokinetics and pharmacodynamics of trandolapril after repeated administration of 2mg to patients with chronic renal failure and healthy control subjects. J Cardiovasc Pharmacol 1994; 23 Suppl. 4: S50–9PubMedGoogle Scholar
  58. 58.
    Stimpel M, Bonn R, Koch B, et al. Pharmacology and clinical use of the new ACE-inhibitor moexipril. Cardiovascular Drug Reviews 1995; 13: 211–29CrossRefGoogle Scholar
  59. 59.
    Stimpel M, Cawello W. Pharmacokinetics and ACE-inhibition of the new ACE-inhibitor moexipril: is coadministration with food of clinical relevance? [abstract]. Hypertension 1995; 25: 1384Google Scholar
  60. 60.
    Grass P, Gerbeau C, Kutz K. Spirapril: pharmacokinetic properties and drug interactions. Blood Press 1994; 3 Suppl. 2: 7–13CrossRefGoogle Scholar
  61. 61.
    Stein G, Sierakowski B, Grass P, et al. Pharmacokinetics of spirapril and spiraprilat in patients with chronic renal failure. Blood Press 1994; 3 Suppl. 2: 47–53CrossRefGoogle Scholar
  62. 62.
    Hayduk K, Kraul H. Efficacy and safety of spirapril in mild-to-moderate hypertension. J Cardiovasc Pharmacol 1999; 34 Suppl. 1: S19–23PubMedCrossRefGoogle Scholar
  63. 63.
    Puchler K, Sierakowski B, Roots I. Single dose and steady state pharmacokinetics of temocapril and temocaprilat in young and elderly hypertensive patients. Br J Clin Pharmacol 1998; 46: 363–7PubMedCrossRefGoogle Scholar
  64. 64.
    Harder S, Thurmann PA, Ungethum W. Single dose and steady state pharmacokinetics and pharmacodynamics of the ACE-inhibitor imidapril in hypertensive patients. Br J Clin Pharmacol 1998; 45: 377–80PubMedCrossRefGoogle Scholar
  65. 65.
    Meyer BH, Muller FO, Badenhorst PN, et al. Multiple doses of trandolapril do not affect warfarin pharmacodynamics. S Afr Med J 1995; 85: 768–70PubMedGoogle Scholar
  66. 66.
    Pritchard G, Lyons D, Webster J, et al. Indomethacin does not attenuate the hypotensive effect of trandolapril. J Hum Hypertens 1996; 10: 763–7PubMedGoogle Scholar
  67. 67.
    Hutt V, Michaelis K, Verbesselt R, et al. Lack of a pharmacokinetic interaction between moexipril and hydrochlorothiazide. Eur J Clin Pharmacol 1996; 51: 339–44PubMedCrossRefGoogle Scholar
  68. 68.
    Van Hecken A, Verbesselt R, Depre M, et al. Moexipril does not alter the pharmacokinetics or pharmacodynamics of warfarin. Eur J Clin Pharmacol 1993; 45: 291–3PubMedCrossRefGoogle Scholar
  69. 69.
    Drugdex ®. Spirapril Drugdex Drug Evaluation. Colorado: Micromedex, Sep 2001.Google Scholar
  70. 70.
    Johnson BF, Wilson J, Johnson J, et al. Digoxin pharmacokinetics and spirapril, a new ACE inhibitor. J Clin Pharmacol 1991; 31: 527–30PubMedGoogle Scholar
  71. 71.
    Sierakowski B, Puchler K, Witte PU, et al. Single-dose pharmacokinetics of temocapril and temocapril diacid in subjects with varying degrees of renal impairment. Eur J Clin Pharmacol 1997; 53: 215–20PubMedCrossRefGoogle Scholar
  72. 72.
    Puchler K, Eckl KM, Fritsche L, et al. Pharmacokinetics of temocapril and temocaprilat after 14 once-daily oral doses of temocapril in hypertensive patients with varying degrees of renal impairment. Br J Clin Pharmacol 1997; 44: 531–6PubMedCrossRefGoogle Scholar
  73. 73.
    Suzuki H, Kawaratani T, Shioya H, et al. Study on pharmacokinetics of a new biliary excreted oral angiotensin converting enzyme inhibitor, temocapril (CS-622) in humans. Biopharm Drug Dispos 1993; 14: 41–50PubMedCrossRefGoogle Scholar
  74. 74.
    Shionoiri H, Naruse M, Minamisawa K, et al. Fosinopril: clinical pharmacokinetics and clinical potential. Clin Pharmacokinet 1997; 32: 460–80PubMedCrossRefGoogle Scholar
  75. 75.
    Hoogkamer JF, Kleinbloesem CH, Nokhodian A, et al. Pharmacokinetics of imidapril and its active metabolite imidaprilat following single dose and during steady state in patients with impaired liver function. Eur J Clin Pharmacol 1997; 51: 489–91PubMedCrossRefGoogle Scholar
  76. 76.
    Harder S, Thurmann PA. Pharmacokinetic and pharmacodynamic interaction trial after repeated oral doses of imidapril and digoxin in healthy volunteers. Br J Clin Pharmacol 1997; 43: 475–80PubMedCrossRefGoogle Scholar
  77. 77.
    The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997; 157: 2413–46CrossRefGoogle Scholar
  78. 78.
    Hansson L, Lindholm LH, Niskanen L. Effect of angiotensin-converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353: 611–6PubMedCrossRefGoogle Scholar
  79. 79.
    Pitt B, Segal R, Martinez FA, et al., for ELITE Study Investigators. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly study, ELITE). Lancet 1997; 349: 747–52PubMedCrossRefGoogle Scholar
  80. 80.
    White CM. Angiotensin-converting-enzyme inhibition in heart failure or after myocardial infarction. Am J Health Syst Pharm 2000; 57 Suppl. 11: S18–25PubMedGoogle Scholar
  81. 81.
    The Heart Outcomes Prevention Evaluation Study Investigators. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 154–60CrossRefGoogle Scholar
  82. 82.
    Manley HJ. Role of angiotensin-converting-enzyme inhibition in patients with renal disease. Am J Health-Syst Pharm 2000; 57 Suppl. 1: S12–8PubMedGoogle Scholar
  83. 83.
    Johnston GD. Dose-response relationships with antihypertensive drugs. Clin Pharmacol Ther 1992; 55: 53–93Google Scholar
  84. 84.
    Corea L, Cardoni O, Fogari R, et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: a comparative study of the efficacy and safety against amlodipine. Clin Pharmacol Ther 1996; 60: 341–6PubMedCrossRefGoogle Scholar
  85. 85.
    Salvetti A, Arzilli F. Chronic dose-response curve of enalapril in essential hypertensives. An Italian multicenter study. Am J Hypertens 1989; 2: 352–4PubMedGoogle Scholar
  86. 86.
    Gomez HJ, Cirillo VJ, Sromovsky JA, et al. Lisinopril dose-response relationship in essential hypertension. Br J Clin Pharmacol 1989; 28: 415–20PubMedCrossRefGoogle Scholar
  87. 87.
    Anderson RJ, Duchin KL, Gore RD, et al. Once-daily fosinopril in the treatment of hypertension. Hypertension 1991; 17: 636–42PubMedCrossRefGoogle Scholar
  88. 88.
    Pool JL. Antihypertensive effect of fosinopril, a new angiotensin converting enzyme inhibitor: findings of the fosinopril study group II. Clin Ther 1990; 12: 520–33PubMedGoogle Scholar
  89. 89.
    Chrysant SG, McDonald RH, Wright JT, et al. Perindopril as monotherapy in hypertension: a multicenter comparison of two dosing regimens. Clin Pharmacol Ther 1993; 53: 479–84PubMedCrossRefGoogle Scholar
  90. 90.
    Drayer JM, Stimpel M, Fox A, et al. The antihypertensive properties of the angiotensin converting enzyme inhibitor moexipril given alone or in combination with a low dose of a diuretic. Am J Ther 1995; 2: 525–31PubMedCrossRefGoogle Scholar
  91. 91.
    Vandenburg MJ, Mackay EM, Dews I, et al. Dose finding studies with imidapril-a new ACE inhibitor. Br J Clin Pharmacol 1994; 37: 265–72PubMedCrossRefGoogle Scholar
  92. 92.
    Sedman AJ, Posvar E. Clinical pharmacology of quinapril in healthy volunteers and in patients with hypertension and congestive heart failure. Angiology 1989; 40: 360–9PubMedGoogle Scholar
  93. 93.
    Weinberger MH, Black HR, Lasseter KC, et al. Diurnal blood pressure in patients with mild-to-moderate hypertension treated with once-daily benazepril. Clin Pharmacol Ther 1990; 47: 608–17PubMedCrossRefGoogle Scholar
  94. 94.
    Guyenne TT, Bellet M, Sassano P, et al. Crossover design for the dose determination of an angiotensin converting enzyme inhibitor in hypertension. J Hypertens 1989; 7: 1005–12CrossRefGoogle Scholar
  95. 95.
    Bellet M, Whalen JJ, Bodin F, et al. Use of crossover trials to obtain antihypertensive dose-response curves and to study combination therapy during the development of benazepril. J Hypertens 1990; 8 Suppl. 4: S43–8Google Scholar
  96. 96.
    Meredith PA, Elliott HL. FDA guidelines on trough: peak ratios in the evaluation of antihypertensive agents. J Cardiovasc Pharmacol 1994; 23 Suppl. 5: S26–30PubMedCrossRefGoogle Scholar
  97. 97.
    Zannad F, Matzinger A, Larche J. Trough/peak ratios of once-daily angiotensin converting enzyme inhibitors and calcium antagonists. Am J Hypertens 1996; 9: 633–43PubMedCrossRefGoogle Scholar
  98. 98.
    Staessen JA, Thijs L, Bijttebier G, et al. Determining the trough-to-peak ratio in parallel-group trials. Hypertension 1997; 29: 659–67PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.Drug Information CenterHartford HospitalHartfordUSA
  2. 2.University of Connecticut School of PharmacyStorrsUSA
  3. 3.Cardiovascular Pharmacology ResearchHartford HospitalHartfordUSA

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