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Clinical Pharmacokinetics

, Volume 20, Issue 4, pp 263–279 | Cite as

Clinical Pharmacokinetics of Ketanserin

  • Bengt Persson
  • Jos Heykants
  • Thomas Hedner
Review Article Drug Disposition

Summary

Ketanserin is a serotonin S2-receptor antagonist introduced for the treatment of arterial hypertension and vasospastic disorders. Plasma concentrations of ketanserin (and some metabolites) can be measured with high performance liquid chromatography using ultraviolet or fluorescence detection, or by radioimmunoassay. The methods are sensitive, accurate and specific. Following oral administration ketanserin is almost completely (more than 98%) and rapidly absorbed and peak concentrations in plasma are reached within 0.5 to 2 hours. It is subject to considerable extraction and metabolism in the liver (first-pass effect) and the absolute bioavailability is around 50%. The compound is extensively distributed to tissues and the volume of distribution is in the order of 3 to 6 L/kg. In plasma ketanserin binds avidly to plasma proteins, mainly albumin, and the free fraction is around 5%. Ketanserin is extensively metabolised and less than 2% is excreted as the parent compound. The major metabolic pathway is by ketone reduction leading to formation of ketanserin-ol which is mainly excreted in the urine. Ketanserin-ol, which by itself does not contribute to the overall pharmacological effect, is partly reoxidised into ketanserin, and it is likely that the terminal half-life of the parent compound is related to the slow ketanserin regeneration from the metabolite.

Following intravenous administration plasma ketanserin concentrations decay triexponentially with sequential half-lives of 0.13, 2 and 14.3h. The terminal half-life is similar after oral administration. Following long term oral dosing (20 or 40mg twice daily) the pharmacokinetics remain linear and steady-state concentrations, which can be predicted from single-dose kinetics, are reached within 4 days. During long term treatment with the common dosage of 40mg twice daily, steady-state concentrations fluctuate between 40 µg/L (trough) and 100 to 140 µg/L (peak). The pharmacokinetic properties of ketanserin are predictable in a wide group of patients and there is no influence from the duration of treatment, age and sex of the patient or concomitant treatment with β-blockers or diuretics. There is no direct relationship between plasma concentrations of ketanserin and the antihypertensive effect in a group of patients. Side effects, including prolongation of the Q-T interval, are dose-dependent and, at least in the individual patient, related to peak plasma concentrations.

In separate studies the pharmacokinetics of ketanserin were investigated in special patient groups, namely the elderly and patients with hepatic and renal insufficiency. In elderly patients over 65 years of age the pharmacokinetics were similar to those found in healthy subjects; if anything, the bioavailability and area under the plasma concentration-time curve tended to be higher in some patients. In patients with severe hepatocellular insufficiency, the bioavailability of ketanserin is markedly higher due to a reduced hepatic elimination; in spite of higher plasma concentrations the terminal half-life is not changed. In view of these observations a higher dosage than 20mg twice daily is not likely to be required. In patients with renal insufficiency, elimination of the metabolite ketanserin-ol is prolonged but adaptation to lower doses of ketanserin is probably not necessary since plasma concentrations of the parent compound are similar to those seen in patients with normal kidney function.

Studies in vitro with ketanserin at concentrations normally seen in patients on long term therapy indicate that ketanserin does not displace other drugs from their protein binding sites in plasma. Conversely, the protein binding of ketanserin is not influenced by the coadministration of other highly bound drugs. There is no evidence that ketanserin induces or reduces hepatic enzyme systems, and it is therefore unlikely that ketanserin treatment will have clinically important effects on the metabolism of concurrently administered drugs, but formal interaction studies are lacking. Combined treatment with propranolol or cimetidine did not influence the pharmacokinetics of ketanserin. Furthermore, ketanserin did not appreciably alter the single-dose pharmacokinetics of digoxin and digitoxin or the steady-state concentrations of digoxin during long term therapy.

Keywords

High Performance Liquid Chromatography Digoxin Clinical Pharmacology Cimetidine Clinical Pharmacokinetic 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Aldariz AE, Romero H, Baroni M, Baglivo H, Esper RJ. QT prolongation and torsade de pointes: ventricular tachycardia produced by ketanserin. Pace 9: 836–841, 1986PubMedCrossRefGoogle Scholar
  2. Andrén L, Svensson A, Dahlöf B, Eggertsen R, Hansson L. Ketanserin in hypertension: early clinical evaluation and dosefinding study of a new 5-HT2 receptor antagonist. Acta Medica Scandinavica 214: 125–130, 1983PubMedCrossRefGoogle Scholar
  3. Barendregt JNM, van Peer A, van der Hoeven JG, Oene JC, Tjandra YI. Ketanserin pharmacokinetics in patients with renal failure. British Journal of Clinical Pharmacology, in press, 1990Google Scholar
  4. Brogden RN, Sorkin EM. Ketanserin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in hypertension and peripheral vascular disease. Drugs 40: 903–949, 1990PubMedCrossRefGoogle Scholar
  5. Cameron HA, Ramsay LE. Ketanserin in essential hypertension: a double-blind, placebo-controlled study. Postgraduate Medical Journal 61: 583–586, 1985PubMedCrossRefGoogle Scholar
  6. Cameron HC, Waller PC, Ramsay LE. The effect of ketanserin on the QT interval. British Journal of Clinical Pharmacology 23: 630P, 1987Google Scholar
  7. Davies CL. Determination of ketanserin in plasma by reversedphase high-performance liquid chromatography. Journal of Chromatography 275: 232–233, 1983PubMedCrossRefGoogle Scholar
  8. De Cree J, Hoing M, De Ryck M, Symoens J. The acute antihypertensive effect of ketanserin increases with age. Journal of Cardiovascular Pharmacology 7 (Suppl. 7): sl26–sl27, 1985Google Scholar
  9. Donnelly R, Elliot HL, Meredith PA, Hughes DMA, Reid JL. Ketanserin concentration-effect relationships in individual hypertensive patients. British Journal of Clinical Pharmacology 26: 61–64, 1988PubMedCrossRefGoogle Scholar
  10. Donnelly R, Elliot HL, Meredith PA, Reid JL. Acute and chronic ketanserin in essential hypertension: antihypertensive mechanisms and pharmacokinetics. British Journal of Clinical Pharmacology 24: 599–606, 1987PubMedCrossRefGoogle Scholar
  11. Doyle AE. Why are the antihypertensive effects of ketanserin age-related? Journal of Cardiovascular Pharmacology 12 (Suppl 8): sl24–sl31, 1988Google Scholar
  12. Fagard R, Cattaert A, Lijnen P, Staessen J, Vanhees L, et al. Responses of the systemic circulation and of the renin-angiotensin-aldosterone system to ketanserin at rest and exercise in normal man. Clinical Science 66: 17–25, 1984PubMedGoogle Scholar
  13. Frenken M, Kaumann AJ. Interaction of ketanserin and its metabolite ketanserinol with 5HT2 receptors in pulmonary and coronary arteries of calf. Naunyn-Schmiedeberg’s Archives of Pharmacology 326: 334–339, 1984PubMedCrossRefGoogle Scholar
  14. Fujita T, Ito Y, Noda H, Isaka M. Antihypertensive effect and pharmacokinetics of KJK-945 (ketanserin tartrate) at single dose on essential hypertension. Journal of Clinical Therapeutics and Medicine 4 (Suppl. I): 21–33, 1988Google Scholar
  15. Gould SE, Silas J, Hosie J. Could the increased antihypertensive efficacy of ketanserin in the elderly be due to altered pharmacokinetics. Cardiovascular Drugs and Therapeutics 4 (Suppl. 1): 87–90, 1990Google Scholar
  16. Hedner T, Andersson OK, Winther K, Persson B. Are there reasons to believe that the antihypertensive effects of serotonin (S2) antagonists are age-related? Journal of Cardiovascular Pharmacology 12 (Suppl. 8): 132–140, 1988Google Scholar
  17. Hedner T, Persson B. Ketanserin in combination with β-adrenergic receptor blocking agents in the treatment of essential hypertension. British Journal of Clinical Pharmacology 18: 765–771, 1984PubMedCrossRefGoogle Scholar
  18. Hedner T, Persson B, Berglund G. Ketanserin, a novel 5-hydroxytrpytamine antagonist: monotherapy in esssential hypertension. British Journal of Clinical Pharmacology 16: 121–125, 1983PubMedCrossRefGoogle Scholar
  19. Hedner T, Persson B, Berglund G. Experience with ketanserin, a serotonin (S2) antagonist, in longterm treatment of essential hypertension. Clinical and Experimental Hypertension A6: 743–751, 1984CrossRefGoogle Scholar
  20. Hedner T, Pettersson A, Persson B. Blood pressure reduction and pharmacokinetics of ketanserin in hypertensive patients. Journal of Hypertension 4 (Suppl. 1): s91–s93, 1986PubMedGoogle Scholar
  21. Heykants J, Michiels M, Woestenborghs R, Awouters F, Leysen JE, et al. Pharmacokinetic evaluation of the in vitro and in vivo pharmacological profile of the major metabolites of ketanserin in the rat. Arzneimittelung-Forschung 38: 785–788, 1988Google Scholar
  22. Heykants J, van Peer A, Woestenborghs R, Gould S, Mills J. Pharmacokinetics of ketanserin and its metabolite ketanserinol in man after intravenous, intramuscular and oral administration. European Journal of Clinical Pharmacology 31: 343–350, 1986PubMedCrossRefGoogle Scholar
  23. Jennings AA, Opie LH. Effects of intravenous ketanserin on severely hypertensive patients with double-blind crossover assessment of central side-effects. Journal of Cardiovascular Pharmacology 9: 120–124, 1987PubMedGoogle Scholar
  24. Kacprowicz AT, Shaw PG, Moulds RFW, Bury RW. Determination of ketanserin in human plasma by high-performance liquid chromatography. Journal of Chromatography 272: 417–420, 1983PubMedCrossRefGoogle Scholar
  25. Kurowski M. Simultaneous determination of ketanserin and ketanserinol in biological fluids using ion-pair liquid chromatography and fluorimetric detection. Journal of Chromatography 341: 208–212, 1985aPubMedCrossRefGoogle Scholar
  26. Kurowski M. Bioavailability and pharmacokinetics of ketanserin in elderly subjects. European Journal of Pharmacology 28: 411–417, 1985bCrossRefGoogle Scholar
  27. Lebrec D, Hadengue A, Gaudin C, Levron JC, Fraitag B, et al. Pharmacokinetics of ketanserin in patients with cirrhosis. Clinical Pharmacokinetics 19: 160–166, 1990PubMedCrossRefGoogle Scholar
  28. Leysen JE, Awouters F, Kennis L, Lauderon PM, Vandenberg J, et al. Receptor binding profile of R41468, a novel antagonist at 5-HT2-receptors. Life Science 28: 1015–1022, 1981CrossRefGoogle Scholar
  29. Lindelauf F. Determination of ketanserin and its major metabolite (reduced ketanserin) in human plasma by high-performance liquid chromatography. Journal of Chromatography 277: 396–400, 1983PubMedCrossRefGoogle Scholar
  30. Longstaff J, Gush R, Williams EH, Jayson MIV. Effect of ketanserin on peripheral blood flow, haemorheology, and platelet function in patients with Raynaud’s phenomenon. Journal of Cardiovascular Pharmacology 7 (Suppl. 7): s99–sl01, 1985PubMedCrossRefGoogle Scholar
  31. McGourty JC, Silas JH, Cowen KJ. Controlled trial of ketanserin in hypertension. British Journal of Clinical Pharmacology 20: 37–40, 1985PubMedCrossRefGoogle Scholar
  32. Meuldermans W, Hendrickx J, Lauwers W, Swysen E, Hurkmans R, et al. Excretion and biotransformation of ketanserin after oral and intravenous administration in rats and dogs. Drug Metabolism and Disposition 12: 772–781, 1984PubMedGoogle Scholar
  33. Meuldermans W, Hendrickx J, Woestenborghs R, van Peer A, Lauwers W, et al. Absorption, metabolism and excretion of ketanserin in man after oral administration. Arzneimittel-Forschung 38: 789–794, 1988aPubMedGoogle Scholar
  34. Meuldermans W, van Houdt J, Mostmans E, Knaeps F, Ver-Luyten W, et al. Plasma protein binding of ketanserin and its distribution in blood. Arzneimittel-Forschung 38: 794–800, 1988bPubMedGoogle Scholar
  35. Milei J, Lemus J, Schiavone M, Lucioni MC. Ketanserin in parental treatment of acute essential hypertension: a dose response curve. Journal of Cardiovascular Pharmacology 10 (Suppl. 3): s96–sl00, 1987PubMedGoogle Scholar
  36. Ochs HR, Greenblatt DJ, Holler M, Labedzky L. The interactions of propranolol and ketanserin. Clinical Pharmacology and Therapeutics 41: 55–60, 1987PubMedCrossRefGoogle Scholar
  37. Ochs HR, Verburg-Ochs B, Holler M, Greenblatt DJ. Effect of ketanserin on the kinetics of digoxin and digitoxin. Journal of Cardiovascular Pharmacology 7: 205–207, 1985PubMedCrossRefGoogle Scholar
  38. Okonkwo PO, Reiman IW, Woestenborghs R, Klotz U. Highperformance liquid chromatographic assay with fluorimetric detection of ketanserin, a new antihypertensive agent and serotonin S2 antagonist in human plasma. Journal of Chromatography 272: 411–416, 1983PubMedCrossRefGoogle Scholar
  39. Onoyama K, Oochi N, Ando T, Fujishima M, Uji Y, et al. Pharmacokinetic properties of ketanserin in patients with chronic renal failure after single-dose oral administration. Current Therapeutic Research 43: 1099–1108, 1988Google Scholar
  40. Persson B, Pettersson A, Hedner T. Pharmacokinetics of ketanserin in patients with essential hypertension. European Journal — of Clinical Pharmacology 32: 259–265, 1987PubMedCrossRefGoogle Scholar
  41. Proppe D, Manthei P. Kinetic und Kardialer Effect von Ketanserin bei Langzeitbehandlung von Hypertonikern mit eingeschränkter Nierenfunktion. Klinische Wochenschrift 67 (Suppl. XVI): 122, 1989Google Scholar
  42. Reimann IW, Frölich JC, Mechanism of antihypertensive action of ketanserin in man. British Medical Journal 287: 381–383, 1983PubMedCrossRefGoogle Scholar
  43. Reimann IW, Okonkwo PO, Klotz U. Pharmacokinetics of ketanserin in man. European Journal of Clinical Pharmacology 25: 73–76, 1983PubMedCrossRefGoogle Scholar
  44. Robertson JIS. Recent insights into the antihypertensive mechanism of action of ketanserin. In: Paoletti et al. (Eds) Serotonin: from cell biology to pharmacology and therapeutics, pp. 411–416, Kluwer Academic Publishers, 1990Google Scholar
  45. Rosendorff C, Murray GD, International Study Group. Ketanserin versus metoprolol and hydrochlorothiazide in essential hypertension: only ketanserin’s hypotensive effect is age-related. Journal of Hypertension 4 (Suppl. 1): s109–s111, 1986Google Scholar
  46. Simon V, Somani P. Rapid method for the determination of ketanserin, a novel antiserotonergic drug by high performance liquid chromatography. Journal of Chromatography 232: 186–191, 1982PubMedCrossRefGoogle Scholar
  47. Stott DJ, McLenachan JM, Ball SG. Ketanserin, the QT interval and autonomic function testing in normal subjects. British Journal of Clinical Pharmacology 21: 84P, 1986Google Scholar
  48. Trenk D, Luehr A, Radkow N, Jänchen E. Lack of effect of propranolol on the steady state levels of ketanserin. Arzneimittel-Forschung 35: 1286–1288, 1988Google Scholar
  49. Trenk D, Mosler A, Kirch W, Meinertz T, Jänchen E. Pharmacokinetics and pharmacodynamics of the 5-HT2 receptor antagonist ketanserin in man. Journal of Cardiovascular Pharmacology 5: 1034–1039, 1983PubMedCrossRefGoogle Scholar
  50. Uji Y, Ikeda M, Deguchi T, Sugimoto T, Kobayashi S. Phase I study of KJK-945 (ketanserin tartrate). Journal of Clinical Therapeutics and Medicine 4 (Suppl. 1): 3–20, 1988Google Scholar
  51. Waller PC, Tucker GT, Ramsay LE. The pharmacokinetics of ketanserin after a single dose and at steady-state in hypertensive subjects. European Journal of Clinical Pharmacology 33: 423–426, 1987aPubMedCrossRefGoogle Scholar
  52. Waller PC, Tucker GT, Ramsay LE. Lack of effect of ketanserin on indices of hepatic enzyme induction. British Journal of Clinical Pharmacology 24: 24, 1987bGoogle Scholar
  53. Vanhoutte P, Amery A, Birkenhager W, Breckenridge A, Buhler F, et al. Serotonergic mechanisms in hypertension. Focus on the effects of ketanserin. Hypertension 11: 111–133, 1988PubMedCrossRefGoogle Scholar
  54. Van Hueten JM, Janssen PAJ, van Beek J, Xhonneaux R, Verbeuren TJ. et al. Vascular effects of ketanserin (R41468), a novel antagonist of 5-HT2 receptors. Journal of Pharmacology and Experimental Therapeutics 218: 217–230, 1981Google Scholar
  55. van Peer A, Woestenborghs R, Embrechts L, Heykants J. Pharmacokinetic approach to equilibrium between ketanserin and ketanserin-ol. European Journal of Clinical Pharmacology 31: 339–342, 1986PubMedCrossRefGoogle Scholar
  56. Williams FM, Leeser JE, Rawlins MD. Pharmacodynamics and pharmacokinetics of single doses of ketanserin and propran-olol alone and in combination in healthy volunteers. British Journal of Clinical Pharmacology 22: 301–308, 1986PubMedCrossRefGoogle Scholar
  57. Woittez AJJ, Wenting GJ, van den Meiracker AA, Ritsema van Eck HJ, Man in’t Veld AJ, et al. Chronic effect of ketanserin in mild to moderate hypertension. Hypertension 8: 167–173, 1986CrossRefGoogle Scholar
  58. Zazgornik J, Scholz N, Kuska J, Minar E. Plasma concentrations of ketanserin in chronic hemodialyzed patients. International Journal of Clinical Pharmacology Therapeutics and Toxicology 24: 674–676, 1986Google Scholar
  59. Zehender M, Meinertz T, Hohnloser S, Geibel A, Hartung J, et al. Incidence and clinical relevance of QT prolongation caused by the new selective serotonin antagonist ketanserin. American Journal of Cardiology 63: 826–832, 1989PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1991

Authors and Affiliations

  • Bengt Persson
    • 1
    • 2
  • Jos Heykants
    • 1
    • 2
  • Thomas Hedner
    • 1
    • 2
  1. 1.Department of Medicine I and Clinical PharmacologySahlgren’s HospitalGothenburgSweden
  2. 2.Department of Drug Metabolism and PharmacokineticsJanssen PharmaceuticaBeerseBelgium

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