Clinical Pharmacokinetics

, Volume 44, Issue 8, pp 797–814

Clinical Pharmacokinetics of Losartan

  • Domenic A. Sica
  • Todd W. B. Gehr
  • Siddhartha Ghosh
Review Article


Losartan is the first orally available angiotensin-receptor antagonist without agonist properties. Following oral administration, losartan is rapidly absorbed, reaching maximum concentrations 1–2 hours post-administration. After oral administration approximately 14% of a losartan dose is converted to the pharmacologically active E 3174 metabolite. E 3174 is 10- to 40-fold more potent than its parent compound and its estimated terminal half-life ranges from 6 to 9 hours. The pharmacokinetics of losartan and E 3174 are linear, dose-proportional and do not substantially change with repetitive administration. The recommended dosage of losartan 50 mg/day can be administered without regard to food. There are no clinically significant effects of age, sex or race on the pharmacokinetics of losartan, and no dosage adjustment is necessary in patients with mild hepatic impairment or various degrees of renal insufficiency. Losartan, or its E 3174 metabolite, is not removed during haemodialysis.

The major metabolic pathway for losartan is by the cytochrome P450 (CYP) 3A4, 2C9 and 2C10 isoenzymes. Overall, losartan has a favorable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between this drug and a range of inhibitors and stimulators of the CYP450 system. Losartan does not have a drug-drug interaction with hydrochlorothiazide, warfarin or digoxin. Losartan should be avoided in pregnancy, as is the case with all other angiotensin-receptor antagonists. When given in the second and third trimester of pregnancy, losartan is often associated with serious fetal toxicity. Losartan is a competitive antagonist that causes a parallel rightward shift of the concentration-contractile response curve to angiotensin-II, while E 3174 is a noncompetitive ‘insurmountable’ antagonist of angiotensin-II.

The maximum recommended daily dose of losartan is 100mg, which can be given as a once-daily dose or by splitting the same total daily dose into two doses. Losartan reduces blood pressure comparably to other angiotensin-receptor antagonists. Losartan has been extensively studied relative to end-organ protection, with studies having been conducted in diabetic nephropathy, heart failure, post-myocardial infarction and hypertensive patients with left ventricular hypertrophy. The results of these studies have been sufficiently positive to support a more widespread use of angiotensin-receptor antagonists in the setting of various end-organ diseases. Losartan, like other angiotensin-receptor antagonists, is devoid of significant adverse effects.


  1. 1.
    Cody RJ. The clinical potential of renin inhibitors and angiotensin antagonists. Drags 1994; 47: 586–98Google Scholar
  2. 2.
    Schalekamp MA, Derkx FH, Van den Meiracker AH. Renin inhibitors, angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists: relationships between blood pressure responses and effects on the renin-angiotensin system. J Hypertens 1992; 10 Suppl. 7: S157–64Google Scholar
  3. 3.
    Brunner HR, Nussberger J, Waeber B. Angiotensin antagonists. Adv Nephrol 1993; 22: 305–27Google Scholar
  4. 4.
    Burnier M, Waeber B, Branner HR. The advantages of angiotensin II antagonism. J Hypertens 1994; 12 Suppl. 2: S7–15Google Scholar
  5. 5.
    Eberhardt RT, Kevak RM, Kang PM, et al. Angiotensin II receptor blockade: an innovative approach to cardiovascular pharmacotherapy. J Clin Pharmacol 1993; 33: 1023–38PubMedGoogle Scholar
  6. 6.
    Laragh JH, Brunner HR. Saralasin in human hypertension: the early experience. Kidney Int 1979; 15: 536–43Google Scholar
  7. 7.
    Timmermans PB, Carini DJ, Chiu AT, et al. Angiotensin II receptor antagonists: from discovery to antihypertensive drugs. Hypertension 1991; 18 Suppl. III: 136–42Google Scholar
  8. 8.
    Timmermans PB, Benfield P, Chiu AT, et al. Angiotensin II receptors and functional correlates. Am J Hypertens 1992; 5: 221–35SGoogle Scholar
  9. 9.
    Wexler RR, Carini DJ, Duncia JV, et al. Rationale for the chemical development of angiotensin II receptor antagonists. Am J Hypertens 1992; 5: 209–20SGoogle Scholar
  10. 10.
    Timmermans PB, Wong PC, Chiu AT, et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993; 45: 205–51PubMedGoogle Scholar
  11. 11.
    Chiu AT, McCall DE, Price WA, et al. In vitro pharmacology of DuP 753. Am J Hypertens 1991; 4: S282–7Google Scholar
  12. 12.
    Wong PC, Tam ST, Herblin WF, et al. Further studies on the selectivity of DuP 753, a nonpeptide angiotensin II receptor antagonist. Eur J Pharmacol 1991; 196: 201–3PubMedGoogle Scholar
  13. 13.
    Yun CH, Lee HS, Lee H, et al. Oxidation of the angiotensin II receptor antagonist losartan (DuP 753) in human liver microsomes: role of cytochrome P4503A (4) in formation of the active metabolite EXP3174. Drug Metab Dispos 1995; 23: 285–9PubMedGoogle Scholar
  14. 14.
    Stearns RA, Miller RR, Doss GA, et al. The metabolism of DuP753, a nonpeptide angiotensin II receptor antagonist by rat, monkey and human liver slices. Drag Metab Dispos 1992; 20: 281–7Google Scholar
  15. 15.
    Stearns RA, Chakravarty PK, Chen R, et al. Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes: role of cytochrome P4502C and 3A subfamily members. Drug Metab Dispos 1995; 23: 207–15PubMedGoogle Scholar
  16. 16.
    Farthing D, Sica DA, Fakhry I, et al. A simple HPLC method for determination of losartan and E-3174 in human plasma, urine, dialysate utilizing midbore chromatography. J Liq Chrom Bio Appl 1997; 704: 374–8Google Scholar
  17. 17.
    Soldner A, Spahn-Langguth H, Mutschier E. HPLC assays to simultaneously determine the angiotensin-AT1 antagonist losartan as well as its main and active metabolite EXP 3174 in biological material of humans and rats. J Pharm Biomed Anal 1998; 16: 863–73PubMedGoogle Scholar
  18. 18.
    Fuchs B, Breithaupt-Grogler K, Belz GG, et al. Comparative pharmacodynamics and pharmacokinetics of candesartan and losartan in man. J Pharm Pharmacol 2000; 52: 1075–83PubMedGoogle Scholar
  19. 19.
    Krieter PA, Colletti AE, Miller RR, et al. Absorption and glucoronidation of the angiotensin II receptor antagonist losartan by the rat intestine. J Pharmacol Exp Ther 1995; 273: 816–22PubMedGoogle Scholar
  20. 20.
    Riddell JG. Bioavailability of candesartan is unaffected by food in healthy volunteers administered candesartan cilexitil. J Hum Hypertens 1997; 11 Suppl. 2: S29–30PubMedGoogle Scholar
  21. 21.
    Tenero D, Martin D, Ilson B, et al. Pharmacokinetics of intravenously and orally administered eprosartan in healthy males: absolute bioavailability and effect of food. Biopharm Drug Dispos 1998; 19: 351–6PubMedGoogle Scholar
  22. 22.
    Bottorff MB, Tenero DM. Pharmacokinetics of eprosartan in healthy subjects, patients with hypertension, and special populations. Pharmacotherapy 1999; 19: 73–8SGoogle Scholar
  23. 23.
    Chapelsky MC, Martin DE, Tenero DM, et al. A dose proportionality study of eprosartan in healthy male volunteers. J Clin Pharmacol 1998; 38: 34–9PubMedGoogle Scholar
  24. 24.
    Vachharajani NN, Shyu WC, Chando TJ, et al. Oral bioavailability and disposition characteristics of irbesartan, an angiotensin antagonist, in healthy volunteers. J Clin Pharmacol 1998; 38: 702–7PubMedGoogle Scholar
  25. 25.
    Vachharajani NN, Shyu WC, Mantha S, et al. Lack of effect of food on the oral bioavailability of irbesartan in healthy male volunteers. J Clin Pharmacol 1998; 38: 433–6PubMedGoogle Scholar
  26. 26.
    Lo MW, Goldberg MR, McCrea JB, et al. Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite, EXP3174 in humans. Clin Pharmacol Ther 1995; 58: 641–9PubMedGoogle Scholar
  27. 27.
    Lo MW, Toh J, Emmert SE, et al. Pharmacokinetics of intravenous and oral losartan in patients with heart failure. J Clin Pharmacol 1998; 38: 525–32PubMedGoogle Scholar
  28. 28.
    Laeis P, Puchler K, Kirch W. The pharmacokinetic and metabolic profile of olmesartan medoxomil limits the risk of clinically relevant drug interaction. J Hypertens 2001; 19 Suppl. 1: S21–32Google Scholar
  29. 29.
    Stangier J, Schmid J, Turck D, et al. Absorption, metabolism, and excretion of intravenously and orally administered [14C] telmisartan in healthy volunteers. J Clin Pharmacol 2000; 40: 1312–22PubMedGoogle Scholar
  30. 30.
    Flesch G, Muller P, Lloyd P. Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man. Eur J Clin Pharmacol 1997; 52: 115–20PubMedGoogle Scholar
  31. 31.
    Kazierad DJ, Martin DE, Blum RA, et al. Effect of fluconazole on the pharmacokinetics of eprosartan and losartan in healthy male volunteers. Clin Pharmacol Ther 1997; 62: 417–25PubMedGoogle Scholar
  32. 32.
    Ohtawa M, Takayama F, Saitoh K, et al. Pharmacokinetics and biochemical efficacy after single and multiple oral administration of losartan, an orally active nonpeptide angiotensin II receptor antagonist, in humans. Br J Clin Pharmacol 1993; 35: 290–7PubMedGoogle Scholar
  33. 33.
    Sica DA, Shaw WC, Lo MW, et al. The pharmacokinetics of losartan in renal insufficiency. J Hypertens 1995. 13 Suppl. 1: S49–52Google Scholar
  34. 34.
    Simpson KL, McClellan KJ. Losartan: a review of its use, with special focus on elderly patients. Drugs Aging 2000; 16: 227–50PubMedGoogle Scholar
  35. 35.
    Christ DD. Human plasma protein binding of the angiotensin II receptor antagonist losartan potassium (DuP 753/MK 954) and its pharmacologically active metabolite EXP3174. J Clin Pharmacol 1995; 35: 515–20PubMedGoogle Scholar
  36. 36.
    Li Z, Bains JS, Ferguson AV. Functional evidence that the angiotensin antagonist losartan crosses the blood-brain barrier in the rat. Brain Res Bull 1993; 30: 33–9PubMedGoogle Scholar
  37. 37.
    Song KF, Zhuo JL, Mendelsohn FA. Access of peripherally administered DuP 753 to rat brain angiotensin II receptors. Br J Pharmacol 1991; 104: 771–2PubMedGoogle Scholar
  38. 38.
    Culman J, von Heyer C, Piepenburg B, et al. Effects of systemic treatment with irbesartan and losartan on central responses to angiotensin II in conscious, normotensive rats. Eur J Pharmacol 1999; 367: 255–65PubMedGoogle Scholar
  39. 39.
    Polidori C, Ciccocioppo R, Nisato D, et al. Evaluation of the ability of irbesartan to cross the blood-brain barrier following acute intragastric treatment. Eur J Pharmacol 1998; 352: 15–21PubMedGoogle Scholar
  40. 40.
    Munafo A, Christen Y, Nussberger J, et al. Drug concentration response relationships in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist. Clin Pharmacol Ther 1992; 51: 513–21PubMedGoogle Scholar
  41. 41.
    Munger MA, Furniss SM. Angiotensin II receptor blockers: novel therapy for heart failure? Pharmacotherapy 1996; 16(2 Pt 2): 59–68SGoogle Scholar
  42. 42.
    Herve F, Urien S, Albengres E, et al. Drug binding in plasma: a summary of recent trends in the study of drug and hormone binding. Clin Pharmacokinet 1994; 26: 44–58PubMedGoogle Scholar
  43. 43.
    Sachinidis A, Ko Y, Weisser P, et al. EXP3174, a metabolite of losartan (MK 954, DuP753) is more potent than losartan in blocking the angiotensin II-induced responses in vascular smooth muscle cells. J Hypertens 1993; 11: 155–62PubMedGoogle Scholar
  44. 44.
    McCrea JB, Cribb A, Rushmore T, et al. Phenotypic and genotypic investigations of a healthy volunteer deficient in the conversion of losartan to its active metabolite E-3174. Clin Pharmacol Ther 1999; 65: 348–52PubMedGoogle Scholar
  45. 45.
    Meadowcroft AM, Williamson KM, Patterson JH, et al. The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers. J Clin Pharmacol 1999; 39: 418–24PubMedGoogle Scholar
  46. 46.
    Kaukonen KM, Olkkola KT, Neuvonen PJ. Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174. Eur J Clin Pharmacol 1998; 53: 445–9PubMedGoogle Scholar
  47. 47.
    Yasar U, Tybring G, Hidestrand M, et al. Role of CYP2C9 polymorphism in losartan oxidation. Drug Metab Dispos 2001; 29: 1051–6PubMedGoogle Scholar
  48. 48.
    Sandwall P, Lo MW, Jonzon B, et al. Lack of polymorphism of the conversion of losartan to its active metabolite E-3174 in extensive and poor metabolizers of debrisoquine (cytochrome P450 2D6) and mephenytoin (cytochrome P450 2C19). Eur J Clin Pharmacol 1999; 55: 279–83PubMedGoogle Scholar
  49. 49.
    Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in vitro and human data. Pharmacogenetics 2002; 12: 251–63PubMedGoogle Scholar
  50. 50.
    Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998; 4: 525–38Google Scholar
  51. 51.
    Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000; 96: 1816–9PubMedGoogle Scholar
  52. 52.
    Sica DA, Fakhry I, Farthing D, et al. Organic anion transport and the renal handling of losartan [abstract]. Am J Hypertens 2002; 15: 178AGoogle Scholar
  53. 53.
    Sasaki M, Fujimura A, Harada K, et al. Clinical pharmacology of multiple-dose losartan, an angiotensin II receptor antagonist, in patients with essential hypertension. J Clin Pharmacol 1996; 36: 403–40PubMedGoogle Scholar
  54. 54.
    Christen Y, Waeber B, Nussberger J, et al. Oral administration of DuP 753, a specific angiotensin II receptor antagonist, to normal male volunteers: inhibition of pressor response to exogenous angiotensin I and II. Circulation 1991; 83: 1333–42PubMedGoogle Scholar
  55. 55.
    Sweet CS, Bradstreet DC, Berman RS, et al. Pharmacodynamic activity of intravenous E-3174, an angiotensin II antagonist in patients with essential hypertension. Am J Hypertens 1994; 7: 1035–40PubMedGoogle Scholar
  56. 56.
    McIntyre M, Caffe SE, Michalak RA, et al. Losartan, an orally active angiotensin (AT1) receptor antagonist: a review of its efficacy and safety in essential hypertension. Pharmacol Ther 1997; 74: 181–94PubMedGoogle Scholar
  57. 57.
    Martinovic J, Benachi A, Laurent N, et al. Fetal toxic effects and angiotensin-II-receptor antagonists. Lancet 2001; 358: 241–2PubMedGoogle Scholar
  58. 58.
    Saji H, Yamanaka M, Hagiwara A, et al. Losartan and fetal toxic effects. Lancet 2001; 357: 363PubMedGoogle Scholar
  59. 59.
    Lambot MA, Vermeylen D, Noel JC. Angiotensin-II-receptor inhibitors in pregnancy. Lancet 2001; 357: 1619–20PubMedGoogle Scholar
  60. 60.
    Spence SG, Allen HL, Cukierski MA, et al. Defining the susceptible period of developmental toxicity for the AT1-selective angiotensin II receptor antagonist losartan in rats. Teratology 1995; 51: 367–82PubMedGoogle Scholar
  61. 61.
    Spence SG, Zacchei AG, Lee LL, et al. Toxicokinetic analysis of losartan during gestation and lactation in the rat. Teratology 1996; 53: 245–52PubMedGoogle Scholar
  62. 62.
    Yang YY, Lin HC, Lee WC, et al. One-week losartan administration increases sodium excretion in cirrhotic patients with and without ascites. J Gastroenterol 2002; 37: 194–9PubMedGoogle Scholar
  63. 63.
    Hulagu S, Senturk O, Erdem A, et al. Effects of losartan, somatostatin and losartan plus somatostatin on portal hemodynamics and renal functions in cirrhosis. Hepatogastroenterology 2002; 49: 783–7PubMedGoogle Scholar
  64. 64.
    Shaw W, Hogg R, Koch V, et al. Losartan and E-3174 pharmacokinetics in hypertensive children and infants [abstract]. J Am Soc Nephrol 2002; 13: 149AGoogle Scholar
  65. 65.
    Nakashima M, Umemura K. The clinical pharmacology of losartan in Japanese subjects and patients. Blood Press 1996; 5 Suppl. 2: 62–6Google Scholar
  66. 66.
    Sekino K, Kubota T, Okada Y, et al. Effect of the single CYP2C9*3 allele on pharmacokinetics and pharmacodynamics of losartan in healthy Japanese subjects. Eur J Clin Pharmacol 2003; 59: 589–92PubMedGoogle Scholar
  67. 67.
    Yoshitani T, Yagi H, Inotsume N, et al. Effect of experimental renal failure on the pharmacokinetics of losartan in rats. Biol Pharm Bull 2002; 25: 1077–83PubMedGoogle Scholar
  68. 68.
    Pedro AA, Gehr TW, Brophy DF, et al. The pharmacokinetics and pharmacodynamics of losartan in continuous ambulatory peritoneal dialysis. J Clin Pharmacol 2000; 40: 389–95PubMedGoogle Scholar
  69. 69.
    Sica DA, Halstenson CE, Gehr TW, et al. Pharmacokinetics and blood pressure response of losartan in end-stage renal disease. Clin Pharmacokinet 2000; 38: 519–26PubMedGoogle Scholar
  70. 70.
    Saruta T, Suzuki H, Kitajima K, et al. Pharmacokinetics of MK-954 (losartan potassium) on hypertensive patients with renal impairment. Rinsho Iyaku 1994; 10 Suppl. 6: 157–71Google Scholar
  71. 71.
    Sica DA, Gehr TWB, Fernandez A. Risk-benefit ratio of angiotensin receptor blockers versus angiotensin converting enzyme inhibitors in end-stage renal disease. Drug Saf 2000; 22: 350–9PubMedGoogle Scholar
  72. 72.
    Tagawa H, Sugimoto T, Saito H, et al. Pharmacokinetics and blood pressure lowering effect of MK-954 (losartan potassium) in hemodialysis patients with hypertension. Jpn J Clin Dialysis 1995; 11: 247–64Google Scholar
  73. 73.
    McCrea JB, Lo MW, Furtek CI, et al. Ketoconazole does not effect the systemic conversion of losartan to E-3174 [abstract]. Clin Pharmacol Ther 1996; 59: 169Google Scholar
  74. 74.
    Williamson KM, Patterson JH, McQueen RH, et al. Effects of erythromycin or rifampin on losartan pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 1998; 63: 316–23PubMedGoogle Scholar
  75. 75.
    Goldberg MR, Lo MW, Bradstreet TE, et al. Effects of cimetidine on pharmacokinetics and pharmacodynamics of losartan, an AT1-selective non-peptide angiotensin II receptor antagonist. Eur J Clin Pharmacol 1995; 49: 115–9PubMedGoogle Scholar
  76. 76.
    Fischer TL, Pieper JA, Graff DW, et al. Evaluation of potential losartan-phenytoin drug interactions in healthy volunteers. Clin Pharmacol Ther 2002; 72: 238–46PubMedGoogle Scholar
  77. 77.
    Goldberg MR, Lo MW, Deutsch PJ, et al. Phenobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174. Clin Pharmacol Ther 1996; 59: 268–74PubMedGoogle Scholar
  78. 78.
    Zaidenstein R, Soback S, Gips M, et al. Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers. Ther Drug Monit 2001; 23: 369–73PubMedGoogle Scholar
  79. 79.
    McCrea JB, Lo MW, Tomasko L, et al. Absence of a pharmacokinetic interaction between losartan and hydrochlorothiazide. J Clin Pharmacol 1995; 35: 1200–6PubMedGoogle Scholar
  80. 80.
    De Smet M, Schoors DF, De Meyer G, et al. Effect of multiple doses of losartan on the pharmacokinetics of single doses of digoxin in healthy volunteers. Br J Clin Pharmacol 1995; 40: 571–5PubMedGoogle Scholar
  81. 81.
    Kong AN, Tomasko L, Waldman SA, et al. Losartan does not affect the pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol 1995; 35: 1008–15PubMedGoogle Scholar
  82. 82.
    Goldberg MR, Bradstreet TE, McWilliams EJ, et al. Biochemical effects of losartan, a nonpeptide angiotensin II receptor antagonist, on the renin-angiotensin-aldosterone system in hypertensive patients. Hypertension 1995; 25: 37–46PubMedGoogle Scholar
  83. 83.
    Mallion JM, Bradstreet DC, Makris L, et al. Antihypertensive efficacy and tolerability of once daily losartan potassium with mild to moderate essential hypertension. J Hypertens 1995; 13 Suppl. 1: S35–41Google Scholar
  84. 84.
    Doig JK, MacFadyen RJ, Sweet CS, et al. Dose-ranging study of the angiotensin type I receptor antagonist losartan (DuP753/ MK954), in salt-deplete normal man. J Cardiovasc Pharmacol 1993; 21: 732–8PubMedGoogle Scholar
  85. 85.
    Goldberg MR, Tanaka W, Barchowsky A, et al. Effects of losartan on blood pressure, plasma renin activity, and angiotensin II in volunteers. Hypertension 1993; 21: 704–13PubMedGoogle Scholar
  86. 86.
    Opsahl J, Goldberg MR, Katz SA. Effect of acute and chronic losartan therapy on active and inactive renin and active renin glycoforms. Am J Hypertens 1995; 8: 1090–8PubMedGoogle Scholar
  87. 87.
    Grossman E, Peleg E, Carroll J, et al. Hemodynamic and humoral effects of the angiotensin II antagonist losartan in essential hypertension. Am J Hypertens 1994; 7: 1041–4PubMedGoogle Scholar
  88. 88.
    Erley CM, Bader B, Scheu M, et al. Renal hemodynamics in essential hypertensives treated with losartan. Clin Nephrol 1995; 43 Suppl. 1: S8–11PubMedGoogle Scholar
  89. 89.
    Doig JK, MacFadyen RJ, Sweet CS, et al. Haemodynamic and renal responses to oral losartan potassium during salt depletion or salt repletion in normal human volunteers. J Cardiovasc Pharmacol 1995; 25: 511–7PubMedGoogle Scholar
  90. 90.
    Tsunoda K, Abe K, Hagino T, et al. Hypotensive effect of losartan, a nonpeptide angiotensin II receptor antagonist, in essential hypertension. Am J Hypertens 1993; 6: 28–32PubMedGoogle Scholar
  91. 91.
    Sasaki M, Fujimura A, Harada K, et al. Effect of losartan, an angiotensin II antagonist, on response of cortisol and aldosterone to adrenocorticotrophic hormone. J Clin Pharmacol 1995; 35: 776–9PubMedGoogle Scholar
  92. 92.
    Azizi M, Chatellier G, Guyene TT, et al. Additive effects of combined angiotensin-converting enzyme inhibition and angiotensin II antagonism on blood pressure and renin release in sodium-depleted normotensives. Circulation 1995; 92: 825–34PubMedGoogle Scholar
  93. 93.
    Wong PC, Price Jr WA, Chiu AT, et al. Nonpeptide angiotensin II receptor antagonists: studies with EXP9270 and DuP 753. Hypertension 1990; 15: 823–34PubMedGoogle Scholar
  94. 94.
    Wong PC, Price WA, Chiu AT, et al. Nonpeptide angiotensin II receptor antagonists: VIII. Characterization of functional antagonism displayed by DuP 753, an orally active antihypertensive agent. J Pharmacol Exp Ther 1990; 252: 719–25PubMedGoogle Scholar
  95. 95.
    Christen Y, Waeber B, Nussberger J, et al. Dose-response relationships following oral administration of DuP 753 to normal humans. Am J Hypertens 1991; 4: 350–4SGoogle Scholar
  96. 96.
    Maillard MP, Wurzner G, Nussberger J, et al. Comparative angiotensin II receptor blockade in healthy volunteers: the importance of dosing. Clin Pharmacol Ther 2002; 71: 68–76PubMedGoogle Scholar
  97. 97.
    Reid JL. Inhibitors of the renin-angiotensin system: clinical pharmacology studies on kinetics, dynamics and concentration-effect relationships. Drug Res 1993; 43: 263–4Google Scholar
  98. 98.
    Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–9PubMedGoogle Scholar
  99. 99.
    Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study - ELITE). Lancet 1997; 349: 747–52PubMedGoogle Scholar
  100. 100.
    Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial: the Losartan Heart Failure Survival Study (ELITE II). Lancet 2000; 355: 1582–7PubMedGoogle Scholar
  101. 101.
    Dickstein K, Kjekshus J, OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002; 360: 752–60PubMedGoogle Scholar
  102. 102.
    Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995–1003PubMedGoogle Scholar
  103. 103.
    Weber MA, Byyny RL, Pratt JH, et al. Blood pressure effects of the angiotensin II receptor blocker, losartan. Arch Intern Med 1995; 155: 405–11PubMedGoogle Scholar
  104. 104.
    Dahlof B, Keller SE, Makris L, et al. Efficacy and tolerability of losartan potassium and atenolol in patients with mild to moderate essential hypertension. Am J Hypertens 1995; 8: 578–83PubMedGoogle Scholar
  105. 105.
    Goa KL, Wagstaff AJ. Losartan potassium: a review of its pharmacology, clinical efficacy and tolerability in the management of hypertension. Drugs 1996; 5: 820–45Google Scholar
  106. 106.
    Mann R, Mackay F, Pearce G, et al. Losartan: a study of pharmacovigilance data on 14,522 patients. J Hum Hypertens 1999; 13: 551–7PubMedGoogle Scholar
  107. 107.
    Sica DA, Gehr TW. The pharmacokinetics and pharmacodynamics of angiotensin-receptor blockers in end-stage renal disease. J Renin Angiotensin Aldosterone Syst 2002; 3: 247–54PubMedGoogle Scholar
  108. 108.
    Bosch X. Henoch-Schonlein purpura induced by losartan therapy. Arch Intern Med 1998; 158: 191–2PubMedGoogle Scholar
  109. 109.
    Heeringa M, van Puijenbroek EP. Reversible dysgeusia attributed to losartan. Ann Intern Med 1998; 129: 72PubMedGoogle Scholar
  110. 110.
    Schlienger RG, Saxer M, Haefeli WE. Reversible ageusia associated with losartan. Lancet 1996; 347: 471–2PubMedGoogle Scholar
  111. 111.
    Ohkoshi N, Shoji S. Reversible ageusia induced by losartan: a case report. Eur J Neurol 2002; 9: 315PubMedGoogle Scholar
  112. 112.
    Ahmad S. Losartan and severe migraine. JAMA 1995; 274: 1266–7PubMedGoogle Scholar
  113. 113.
    Ahmad S. Losartan and reversible psychosis. Cardiology 1996; 87: 569–70PubMedGoogle Scholar
  114. 114.
    Etminan M, Levine MA, Tomlinson G, et al. Efficacy of angiotensin II receptor antagonists in preventing headache: a systematic overview and meta-analysis. Am J Med 2002; 112: 642–6PubMedGoogle Scholar
  115. 115.
    Tabak F, Mert A, Ozaras R, et al. Losartan-induced hepatic injury. J Clin Gastroenterol 2002; 34: 585–6PubMedGoogle Scholar
  116. 116.
    Llisterri JL, Lozano Vidal JV, Aznar Vicente J, et al. Sexual dysfunction in hypertensive patients treated with losartan. Am J Med Sci 2001; 321: 336–41PubMedGoogle Scholar
  117. 117.
    Acker CG, Greenberg A. Angioedema induced by the angiotensin II blocker losartan [letter]. N Engl J Med 1995; 333: 1572PubMedGoogle Scholar
  118. 118.
    Boxer M. Accupril and cozaar-induced angioedema in the same patient [letter]. J Allergy Clin Immunol 1996; 98: 471PubMedGoogle Scholar
  119. 119.
    Sharma PK, Yium JJ. Angioedema associated with angiotensin II receptor antagonist losartan. South Med J 1997; 90: 552–3PubMedGoogle Scholar
  120. 120.
    van Rijnsoever EW, Kwee-Zuiderwijk WJ, Feenstra J. Angioneurotic edema attributed to the use of losartan. Arch Intern Med 1998; 158: 2063–5PubMedGoogle Scholar
  121. 121.
    Fuchs SA, Koopmans RP, Guchellaar HJ. Are angiotensin-II receptor antagonists safe in patients with previous angiotensinconverting enzyme inhibitor-induced angioedema [letter]. Hypertension 2001; 37: ElGoogle Scholar
  122. 122.
    Sica DA, Black HR. Current concepts of pharmacotherapy in hypertension: ACE inhibitor-related angioedema: can angiotensin-receptor blockers be safely used? J Clin Hypertens (Greenwich) 2002; 4: 375–80Google Scholar
  123. 123.
    Chiu AG, Krowiak EJ, Deeb ZE. Angioedema associated with angiotensin II receptor antagonists: challenging our knowledge of angioedema and its etiology. Laryngoscope 2001; 111: 1729–31PubMedGoogle Scholar
  124. 124.
    Warner KK, Visconti JA, Tschampel MM. Angiotensin II receptor blockers in patients with ACE inhibitor-induced angioedema. Ann Pharmacother 2000; 34: 526–8PubMedGoogle Scholar
  125. 125.
    Sica DA, Black HR. Angioedema in heart failure: occurrence with ACE inhibitors and safety of angiotensin receptor blocker therapy. Congest Heart Fail 2002; 8: 334-41, 345Google Scholar
  126. 126.
    Gansevoort RT, de Zeeuw D, Shahinfar S, et al. Effects of the angiotensin II antagonist losartan in hypertensive patients with renal disease. J Hypertens Suppl 1994; 12: S37–42PubMedGoogle Scholar
  127. 127.
    Toto R, Shultz P, Raij L, et al. Efficacy and tolerability of losartan in hypertensive patients with renal impairment. Collaborative Group. Hypertension 1998; 31: 684–91PubMedGoogle Scholar
  128. 128.
    Soffer BA, Wright JT, Pratt JH, et al. Effects of losartan on a background of hydrochlorothiazide in patients with hypertension. Hypertension 1995; 26: 112–7PubMedGoogle Scholar
  129. 129.
    Sica DA, Schoolwerth AC. Uric acid and losartan (Pt 1). Curr Opin Nephrol Hypertens 2002; 11: 475–82PubMedGoogle Scholar
  130. 130.
    Shahinfar S, Simpson RL, Carides AD, et al. Safety of losartan in hypertensive patients with thiazide-induced hyperuricemia. Kidney Int 1999; 56: 1879–85PubMedGoogle Scholar
  131. 131.
    Schoolwerth AC, Sica DA, Ballermann BJ, et al. Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association. Circulation 2001; 104: 1985–91PubMedGoogle Scholar
  132. 132.
    Toto R. Angiotensin II subtype 1-receptor blockers and renal function. Arch Intern Med 2001; 161: 1492–9PubMedGoogle Scholar
  133. 133.
    Maillard JO, Descombes E, Fellay G, et al. Repeated transient anuria following losartan administration in a patient with a solitary kidney. Ren Fail 2001; 23: 143–7PubMedGoogle Scholar
  134. 134.
    Cohen LS, Friedman EA. Losartan-induced azotemia in a diabetic recipient of a kidney transplant. N Engl J Med 1996; 334: 1271–2PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  • Domenic A. Sica
    • 1
  • Todd W. B. Gehr
    • 1
  • Siddhartha Ghosh
    • 1
  1. 1.Division of Nephrology, MCV Station, Medical College of VirginiaVirginia Commonwealth UniversityRichmondUSA

Personalised recommendations