Clinical Pharmacokinetics

, Volume 43, Issue 4, pp 227–238

Comparative Pharmacokinetics and Pharmacodynamics of Short-Acting Hypnosedatives

Zaleplon, Zolpidem and Zopiclone
Review Article


Benzodiazepines have historically been the mainstay of treatment for sleeping disorders, yet they have many shortcomings. A new group of sedative hypnotic agents has been developed for this purpose. Similar to the benzodiazepines, zaleplon, zolpidem and zopiclone have activity at the GABA receptor complex, yet they appear to have more selectivity for certain subunits of the GABA receptor. This produces a clinical profile that is more efficacious with fewer side effects. Zaleplon, zolpidem and zopiclone are structurally distinct. Due to variation in binding to the GABA receptor subunits, these three compounds show subtle differences in their effect on sleep stages, and as antiepileptics, anxiolytics and amnestics.

The duration of action of zaleplon, zolpidem and zopiclone can be related to their individual pharmacokinetic profile, which subsequently determines the time course of drug effect. Each of these compounds has a unique pharmacokinetic profile with different bioavailability, volume of distribution and elimination half-lives. Zaleplon has a rapid elimination so there are fewer residual side effects after taking a single dose at bedtime. By comparison, zolpidem and zopiclone have a more delayed elimination so there may be a prolonged drug effect. This can result in residual sedation and side effects but may be useful for sustained treatment of insomnia with less waking during the night. There are also differences in potency based on plasma concentrations suggesting that there are differences in binding to the GABA receptor complex. Although zaleplon has a much lower bioavailability (30%), the treatment dose is similar to zolpidem and zopiclone (bioavilaibility of 70%) because of the increased potency of zaleplon.

The pharmacokinetics and pharmacodynamics of zaleplon, zolpidem and zopiclone are significantly different from benzodiazepines. The new drugs are sufficiently unique from each other to allow customisation of treatment for various types of insomnia. While zaleplon may be best indicated for the delayed onset of sleep, zolpidem and zopiclone may be better indicated for maintaining a complete night’s sleep. Only the patient’s symptoms and response to treatment will dictate the best course of treatment.


  1. 1.
    Mendelson WB, Jain B. An assessment of short-acting hypnotics. Drug Saf 1995; 13(4): 257–70PubMedCrossRefGoogle Scholar
  2. 2.
    George CF. Pyrazolopyrimidines. Lancet 2001; 358(9293): 1623–6PubMedCrossRefGoogle Scholar
  3. 3.
    Sieghart W, Sperk G. Subunit composition, distribution and function of GABAA receptor subtypes. Curr Top Med Chem 2002; 2(8): 795–816PubMedCrossRefGoogle Scholar
  4. 4.
    Sieghart W, Fuchs K, Tretter V, et al. Structure and subunit composition of GABAA receptors. Neurochem Int 1999; 34(5): 379–85PubMedCrossRefGoogle Scholar
  5. 5.
    Sieghart W. Structure and pharmacology of γ-aminobutyric acidA receptor subtypes. Pharmacol Rev 1995; 47(2): 181–234PubMedGoogle Scholar
  6. 6.
    Terzano MG, Rossi M, Palomba V, et al. New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon. Drug Saf 2003; 26(4): 261–82PubMedCrossRefGoogle Scholar
  7. 7.
    Wagner J, Wagner ML. Non-benzodiazepines for the treatment of insomnia. Sleep Med Rev 2000; 4(6): 551–81PubMedCrossRefGoogle Scholar
  8. 8.
    Weitzel KW, Wickman JM, Augustin SG, et al. Zaleplon: a pyrazolopyrimidine sedative-hypnotic agent for the treatment of insomnia. Clin Ther 2000; 22(11): 1254–67PubMedCrossRefGoogle Scholar
  9. 9.
    Dooley M, Plosker GL. Zaleplon: a review of its use in the treatment of insomnia. Drugs 2000; 60(2): 413–45PubMedCrossRefGoogle Scholar
  10. 10.
    Hoehns JD, Perry PJ. Zolpidem: a nonbenzodiazepine hypnotic for treatment of insomnia. Clin Pharm 1993; 12(11): 814–28PubMedGoogle Scholar
  11. 11.
    Langtry HD, Benfield P. Zolpidem: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 1990; 40(2): 291–313PubMedCrossRefGoogle Scholar
  12. 12.
    Holm KJ, Goa KL. Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. Drugs 2000; 59(4): 865–89PubMedCrossRefGoogle Scholar
  13. 13.
    Goa KL, Heel RC. Zopiclone: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as an hypnotic. Drugs 1986; 32(1): 48–65PubMedCrossRefGoogle Scholar
  14. 14.
    Noble S, Langtry HD, Lamb HM. Zopiclone: an update of its pharmacology, clinical efficacy and tolerability in the treatment of insomnia. Drugs 1998; 55(2): 277–302PubMedCrossRefGoogle Scholar
  15. 15.
    Kales A, Manfredi RL, Vgontzas AN, et al. Rebound insomnia after only brief and intermittent use of rapidly eliminated benzodiazepines. Clin Pharmacol Ther 1991; 49(4): 468–76PubMedCrossRefGoogle Scholar
  16. 16.
    Kales A, Soldatos CR, Bixler EO, et al. Midazolam: doseresponse studies of effectiveness and rebound insomnia. Pharmacology 1983; 26(3): 138–49PubMedCrossRefGoogle Scholar
  17. 17.
    Damgen K, Leddens H. Zaleplon displays a selectivity to recombinant GABAA receptors different from zolpidem, zopiclone and benzodiazepines. Neurosci Res Commun 1999; 25(3): 139–48CrossRefGoogle Scholar
  18. 18.
    Sanger DJ, Zivkovic B. Further behavioural evidence for the selective sedative action of zolpidem. Neuropharmacology 1988; 27(11): 1125–30PubMedCrossRefGoogle Scholar
  19. 19.
    Vanover KE, Barrett JE. Evaluation of the discriminative stimulus effects of the novel sedative-hypnotic CL 284,846. Psycho-pharmacology (Berl) 1994; 115(3): 289–96CrossRefGoogle Scholar
  20. 20.
    Day IP, Clody DE, Monaghan MM, et al. Pharmacology of CL 284,846 a non-benzodiazepine sedative with reduced amnestic liability [abstract]. Soc Neurosci 1992; 18: 725Google Scholar
  21. 21.
    Griebel G, Perrault G, Letang V, et al. New evidence that the pharmacological effects of benzodiazepine receptor ligands can be associated with activities at different BZω receptor subtypes. Psychopharmacology (Berl) 1999; 146(2): 205–13CrossRefGoogle Scholar
  22. 22.
    Noguchi H, Kitazumi K, Mori M, et al. Binding and neuropharmacological profile of zaleplon, a novel nonbenzodiazepine sedative/hypnotic. Eur J Pharmacol 2002; 434(1–2): 21–8PubMedCrossRefGoogle Scholar
  23. 23.
    Drover D, Lemmens H, Naidu S, et al. Pharmacokinetics, pharmacodynamics, and relative pharmacokinetic/pharmacodynamic profiles of zaleplon and zolpidem. Clin Ther 2000; 22(12): 1443–61PubMedCrossRefGoogle Scholar
  24. 24.
    McMahon LR, Gerak LR, Carter L, et al. Discriminative stimulus effects of benzodiazepine BZ1 receptor-selective ligands in rhesus monkeys. J Pharmacol Exp Ther 2002; 300(2): 505–12PubMedCrossRefGoogle Scholar
  25. 25.
    Sanger DJ. The effects of new hypnotic drugs in rats trained to discriminate ethanol. Behav Pharmacol 1997; 8(4): 287–92PubMedCrossRefGoogle Scholar
  26. 26.
    Sanger DJ. Behavioural effects of novel benzodiazepine (omega) receptor agonists and partial agonists: increases in punished responding and antagonism of the pentylenetetrazole cue. Behav Pharmacol 1995; 6(2): 116–26PubMedCrossRefGoogle Scholar
  27. 27.
    Davies M, Newell JG, Derry JM, et al. Characterization of the interaction of zopiclone with γ-aminobutyric acid type A receptors. Mol Pharmacol 2000; 58(4): 756–62PubMedGoogle Scholar
  28. 28.
    Blanchard JC, Zundel JL, Julou L. Differences between cyclopyrrolones (suriclone and zopiclone) and benzodiazepine binding to rat hippocampus photolabelled membranes. Biochem Pharmacol 1983; 32(23): 3651–3PubMedCrossRefGoogle Scholar
  29. 29.
    Blanchard JC, Boireau A, Julou L. Brain receptors and zopiclone. Pharmacology 1983; 27 Suppl. 2: 59–69PubMedCrossRefGoogle Scholar
  30. 30.
    Blanchard JC, Boireau A, Garret C, et al. In vitro and in vivo inhibition by zopiclone of benzodiazepine binding to rodent brain receptors. Life Sci 1979; 24(26): 2417–20PubMedCrossRefGoogle Scholar
  31. 31.
    Visser SA, Wolters FL, Van Der Graaf PH, et al. Dosedependent EEG effects of zolpidem provide evidence for GABAA receptor subtype selectivity in vivo. J Pharmacol Exp Ther 2003; 304(3): 1251–7PubMedCrossRefGoogle Scholar
  32. 32.
    Visser SA, Wolters FL, Gubbens-Stibbe JM, et al. Mechanismbased pharmacokinetic/pharmacodynamic modeling of the electroencephalogram effects of GABAA receptor modulators: in vitro-in vivo correlations. J Pharmacol Exp Ther 2003; 304(1): 88–101PubMedCrossRefGoogle Scholar
  33. 33.
    Follesa P, Mancuso L, Biggio F, et al. Changes in GABAA receptor gene expression induced by withdrawal of, but not by long-term exposure to, zaleplon or zolpidem. Neuropharmacology 2002; 42(2): 191–8PubMedCrossRefGoogle Scholar
  34. 34.
    Danjou P, Paty I, Fruncillo R, et al. A comparison of the residual effects of zaleplon and zolpidem following administration 5 to 2h before awakening. Br J Clin Pharmacol 1999; 48(3): 367–74PubMedCrossRefGoogle Scholar
  35. 35.
    Walsh JK, Pollak CP, Scharf MB, et al. Lack of residual sedation following middle-of-the-night zaleplon administration in sleep maintenance insomnia. Clin Neuropharmacol 2000; 23(1): 17–21PubMedCrossRefGoogle Scholar
  36. 36.
    Vermeeren A, Riedel WJ, van Boxtel MP, et al. Differential residual effects of zaleplon and zopiclone on actual driving: a comparison with a low dose of alcohol. Sleep 2002; 25(2): 224–31PubMedGoogle Scholar
  37. 37.
    Hedner J, Yaeche R, Emilien G, et al. Zaleplon shortens subjective sleep latency and improves subjective sleep quality in elderly patients with insomnia. The Zaleplon Clinical Investigator Study Group. Int J Geriate Psychiatry 2000; 15(8): 704–12CrossRefGoogle Scholar
  38. 38.
    Elie R, Ruther E, Farr I, et al. Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic: Zaleplon Clinical Study Group. J Clin Psychiatry 1999; 60(8): 536–44PubMedCrossRefGoogle Scholar
  39. 39.
    Uchiumi M, Isawa S, Suzuki M, et al. The effects of zolpidem and zopiclone on daytime sleepiness and psychomotor performance. Nihon Shinkei Seishin Yakurigaku Zasshi 2000; 20(3): 123–30PubMedGoogle Scholar
  40. 40.
    Dietrich B, Emilien G, Salinas E. Zaleplon does not produce residual sedation in a phase-advance model of transient insomnia [abstract]. J Sleep Res 1998; 7 Suppl. 2: 67Google Scholar
  41. 41.
    Hemmeter U, Muller M, Bischof R, et al. Effect of zopiclone and temazepam on sleep EEG parameters, psychomotor and memory functions in healthy elderly volunteers. Psychopharmacology (Berl) 2000; 147(4): 384–96CrossRefGoogle Scholar
  42. 42.
    Nakajima T, Sasaki T, Nakagome K, et al. Comparison of the effects of zolpidem and zopiclone on nocturnal sleep and sleep latency in the morning: a cross-over study in healthy young volunteers. Life Sci 2000; 67(1): 81–90PubMedCrossRefGoogle Scholar
  43. 43.
    Hajak G. A comparative assessment of the risks and benefits of zopiclone: a review of 15 years clinical experience. Drug Saf 1999; 21(6): 457–69PubMedCrossRefGoogle Scholar
  44. 44.
    Hajak G, Clarenbach P, Fischer W, et al. Zopiclone improves sleep quality and daytime well-being in insomniac patients: comparison with triazolam, flunitrazepam and placebo. Int Clin Psychopharmacol 1994; 9(4): 251–61PubMedCrossRefGoogle Scholar
  45. 45.
    Voderholzer U, Riemann D, Hornyak M, et al. A double-blind, randomized and placebo-controlled study on the polysomnographic withdrawal effects of zopiclone, zolpidem and triazolam in healthy subjects. Eur Arch Psychiatry Clin Neurosci 2001; 251(3): 117–23PubMedCrossRefGoogle Scholar
  46. 46.
    Sanger DJ, Morel E, Perrault G. Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and zolpidem. Eur J Pharmacol 1996; 313(1–2): 35–42PubMedCrossRefGoogle Scholar
  47. 47.
    Gaudreault J, Varin F, Pollack GM. Pharmacokinetics and anticonvulsant effect of a new hypnotic, CL 284,846, in rats. Pharm Res 1995; 12(11): 1592–7PubMedCrossRefGoogle Scholar
  48. 48.
    Julou L, Bardone MC, Blanchard JC, et al. Pharmacological studies on zopiclone. Pharmacology 1983; 27 Suppl. 2: 46–58PubMedCrossRefGoogle Scholar
  49. 49.
    Griebel G, Perrault G, Sanger DJ. Differences in anxiolytic-like profile of two novel nonbenzodiazepine BZ (omega) receptor agonists on defensive behaviors of mice. Pharmacol Biochem Behav 1999; 62(4): 689–94PubMedCrossRefGoogle Scholar
  50. 50.
    Lobarinas E, Falk JL. Comparison of benzodiazepines and the non-benzodiazepine agents zolpidem and zaleplon with respect to anxiolytic action as measured by increases in hypertonic NaCl-solution drinking in rats. Psychopharmacology (Berl) 2000; 149(2): 176–80CrossRefGoogle Scholar
  51. 51.
    Depoortere H, Zivkovic B, Lloyd KG, et al. Zolpidem, a novel nonbenzodiazepine hypnotic: I. neuropharmacological and behavioral effects. J Pharmacol Exp Ther 1986; 237(2): 649–58Google Scholar
  52. 52.
    Berson A, Descatoire V, Sutton A, et al. Toxicity of alpidem, a peripheral benzodiazepine receptor ligand, but not zolpidem, in rat hepatocytes: role of mitochondrial permeability transition and metabolic activation. J Pharmacol Exp Ther 2001; 299(2): 793–800PubMedGoogle Scholar
  53. 53.
    Griebel G, Perrault G, Sanger DJ. Limited anxiolytic-like effects of non-benzodiazepine hypnotics in rodents. J Psychopharmacol 1998; 12(4): 356–65PubMedCrossRefGoogle Scholar
  54. 54.
    Carlson JN, Haskew R, Wacker J, et al. Sedative and anxiolytic effects of zopiclone’s enantiomers and metabolite. Eur J Pharmacol 2001; 415(2-3): 181–9PubMedCrossRefGoogle Scholar
  55. 55.
    Georgiev V. (S)-Zopiclone (Sepracor). Curr Opin Investig Drugs 2001; 2(2): 271–3PubMedGoogle Scholar
  56. 56.
    Ghoneim MM, Mewaldt SP, Berie JL, et al. Memory and performance effects of single and 3-week administration of diazepam. Psychopharmacology 1981; 73(2): 147–51PubMedCrossRefGoogle Scholar
  57. 57.
    Curran HV. Tranquillising memories: a review of the effects of benzodiazepines on human memory. Biol Psychol 1986; 23(2): 179–213PubMedCrossRefGoogle Scholar
  58. 58.
    Troy SM, Lucki I, Unruh MA, et al. Comparison of the effects of zaleplon, zolpidem, and triazolam on memory, learning, and psychomotor performance. J Clin Psychopharmacol 2000; 20(3): 328–37PubMedCrossRefGoogle Scholar
  59. 59.
    File SE, Lister RG. Do lorazepam-induced deficits in learning result from impaired rehearsal, reduced motivation or increased sedation? Br J Clin Pharmacol 1982; 14(4): 545–50PubMedCrossRefGoogle Scholar
  60. 60.
    Beer B, Ieni JR, Wu WH, et al. A placebo-controlled evaluation of single, escalating doses of CL 284,846, a non-benzodiazepine hypnotic. J Clin Pharmacol 1994; 34(4): 335–44PubMedGoogle Scholar
  61. 61.
    Rush CR, Frey JM, Griffiths RR. Zaleplon and triazolam in humans: acute behavioral effects and abuse potential. Psychopharmacology (Berl) 1999; 145(1): 39–51CrossRefGoogle Scholar
  62. 62.
    Isawa S, Suzuki M, Uchiumi M, et al. The effect of zolpidem and zopiclone on memory. Nihon Shinkei Seishin Yakurigaku Zasshi 2000; 20(2): 61–9PubMedGoogle Scholar
  63. 63.
    Dingemanse J, Bury M, Hussain Y, et al. Comparative tolerability, pharmacodynamics, and pharmacokinetics of a metabolite of a quinolizinone hypnotic and zolpidem in healthy subjects. Drug Metab Dispos 2000; 28(12): 1411–6PubMedGoogle Scholar
  64. 64.
    Dingemanse J, Bury M, Bock J, et al. Comparative pharmacodynamics of Ro 41-3696, a new hypnotic, and zolpidem after night-time administration to healthy subjects. Psychopharmacology (Berl) 1995; 122(2): 169–74CrossRefGoogle Scholar
  65. 65.
    Greenblatt DJ, Harmatz JS, von Moltke LL, et al. Comparative kinetics and response to the benzodiazepine agonists triazolam and zolpidem: evaluation of sex-dependent differences. J Pharmacol Exp Ther 2000; 293(2): 435–43PubMedGoogle Scholar
  66. 66.
    Subhan Z, Hindmarch I. Effects of zopiclone and benzodiazepine hypnotics on search in short- term memory. Neuropsychobiology 1984; 12(4): 244–8PubMedCrossRefGoogle Scholar
  67. 67.
    Fossen A, Godlibsen OB, Loyning Y, et al. Effects of hypnotics on memory. Pharmacology 1983; 27 Suppl. 2: 116–26PubMedCrossRefGoogle Scholar
  68. 68.
    Morton S, Lader M. Studies with alpidem in normal volunteers and anxious patients. Pharmacopsychiatry 1990; 23 Suppl. 3: 120–3PubMedCrossRefGoogle Scholar
  69. 69.
    Morton S, Lader M. Alpidem and lorazepam in the treatment of patients with anxiety disorders: comparison of physiological and psychological effects. Pharmacopsychiatry 1992; 25(4): 177–81PubMedCrossRefGoogle Scholar
  70. 70.
    Vidailhet P, Kazes M, Danion JM, et al. Effects of lorazepam and diazepam on conscious and automatic memory processes. Psychopharmacology (Berl) 1996; 127(1): 63–72CrossRefGoogle Scholar
  71. 71.
    Greenblatt DJ, Harmatz JS, von Moltke LL, et al. Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo. Clin Pharmacol Ther 1998; 64(5): 553–61PubMedCrossRefGoogle Scholar
  72. 72.
    Allen D, Curran HV, Lader M. The effects of single doses of CL284,846, lorazepam, and placebo on psychomotor and memory function in normal male volunteers. Eur J Clin Pharmacol 1993; 45(4): 313–20PubMedCrossRefGoogle Scholar
  73. 73.
    Bhatia SC, Arora M, Bhatia SK. Perceptual disturbances with zaleplon. Psychiatr Serv 2001; 52(1): 109–10PubMedCrossRefGoogle Scholar
  74. 74.
    Musch B, Maillard F. Zopiclone, the third generation hypnotic: a clinical overview. Int Clin Psychopharmacol 1990; 5 Suppl. 2: 147–58PubMedGoogle Scholar
  75. 75.
    Delahaye C, Ferrand B, Pieddeloup C, et al. Post marketing surveillance of zopiclone: interim analysis on the first 10,000 cases in a clinical study in general practice. Int Clin Psychopharmacol 1990; 5 Suppl. 2: 131–8PubMedGoogle Scholar
  76. 76.
    Bianchetti G, Dubruc C, Thiercelin JF, et al. Clinical pharmacokinetic of zolpidem in various physiological and pathological conditions. In: Sauvanet JP, Langer SZ, Morelli PL, editors. Imidazopyridines in sleep disorders. New York: Raven Press, 1988: 155–63Google Scholar
  77. 77.
    Gaillot J, Le Roux Y, Houghton GW, et al. Critical factors for pharmacokinetics of zopiclone in the elderly and in patients with liver and renal insufficiency. Sleep 1987; 10 Suppl. 1: 7–21PubMedGoogle Scholar
  78. 78.
    Greenblatt DJ, Harmatz JS, Shader RI. Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly: therapeutic considerations (Part II). Clin Pharmacokinet 1991; 21(4): 262–73PubMedCrossRefGoogle Scholar
  79. 79.
    Greenblatt DJ, Harmatz JS, Shader RI. Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly: therapeutic considerations (Part I). Clin Pharmacokinet 1991; 21(3): 165–77PubMedCrossRefGoogle Scholar
  80. 80.
    Rosen AS, Fournie P, Darwish M, et al. Zaleplon pharmacokinetics and absolute bioavailability. Biopharm Drug Dispos 1999; 20(3): 171–5PubMedCrossRefGoogle Scholar
  81. 81.
    Durand A, Thenot JP, Bianchetti G, et al. Comparative pharmacokinetic profile of two imidazopyridine drugs: zolpidem and alpidem. Drug Metab Rev 1992; 24(2): 239–66PubMedCrossRefGoogle Scholar
  82. 82.
    Thenot JP, Herman P, Durand A, et al. Pharmacokinetics and metabolism of zolpidem in various animal species and in humans. In: Sauvanet JP, Langer SZ, Morelli PL, editors. Imidazopyridines in sleep disorders. New York: Raven Press, 1988: 139–53Google Scholar
  83. 83.
    Patat A, Trocherie S, Thebault JJ, et al. EEG profile of intravenous zolpidem in healthy volunteers. Psychopharmacology (Berl) 1994; 114(1): 138–46CrossRefGoogle Scholar
  84. 84.
    Gaillot J, Heusse D, Hougton GW, et al. Pharmacokinetics and metabolism of zopiclone. Pharmacology 1983; 27 Suppl. 2: 76–91PubMedCrossRefGoogle Scholar
  85. 85.
    Fernandez C, Martin C, Gimenez F, et al. Clinical pharmacokinetics of zopiclone. Clin Pharmacokinet 1995; 29(6): 431–41PubMedCrossRefGoogle Scholar
  86. 86.
    Renwick AB, Mistry H, Ball SE, et al. Metabolism of zaleplon by human hepatic microsomal cytochrome P450 isoforms. Xenobiotica 1998; 28(4): 337–48PubMedCrossRefGoogle Scholar
  87. 87.
    Houghton GW, Dennis MJ, Templeton R, et al. A repeated dose pharmacokinetic study of a new hypnotic agent, zopiclone (Imovane). Int J Clin Pharmacol Ther Toxicol 1985; 23(2): 97–100PubMedGoogle Scholar
  88. 88.
    Fernandez C, Maradeix V, Gimenez F, et al. Pharmacokinetics of zopiclone and its enantiomers in Caucasian young healthy volunteers. Drug Metab Dispos 1993; 21(6): 1125–8PubMedGoogle Scholar
  89. 89.
    Wickland C, Patat A. The safety and pharmacokinetics of zaleplon in hepatically impaired patients [abstract]. Sleep Res Online 1999; 2 Suppl. 1: 171Google Scholar
  90. 90.
    Parker G, Roberts CJ. Plasma concentrations and central nervous system effects of the new hypnotic agent zopiclone in patients with chronic liver disease. Br J Clin Pharmacol 1983; 16(3): 259–65PubMedCrossRefGoogle Scholar
  91. 91.
    Wickland C, Patat A. The pharmacokinetics and safety of zaleplon in patients with renal impairment [abstract]. Sleep Res Online 1999; 2 Suppl. 1: 172Google Scholar
  92. 92.
    Fillastre JP, Geffroy-Josse S, Etienne I, et al. Pharmacokinetics and pharmacodynamics of zolpidem following repeated doses in hemodialyzed uraemic patients. Fundam Clin Pharmacol 1993; 7(1): 1–9PubMedCrossRefGoogle Scholar
  93. 93.
    Pacifici GM, Viani A, Rizzo G, et al. Plasma protein binding of zolpidem in liver and renal insufficiency. Int J Clin Pharmacol Ther Toxicol 1988; 26(9): 439–43PubMedGoogle Scholar
  94. 94.
    Viron B, De Meyer M, Le Liboux A, et al. Steady state pharmacokinetics of zopiclone during multiple oral dosing (7.5mg nocte) in patients with severe chronic renal failure. Int Clin Psychopharmacol 1990; 5 Suppl. 2: 95–104PubMedGoogle Scholar
  95. 95.
    Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000; 38(1): 41–57PubMedCrossRefGoogle Scholar
  96. 96.
    Hetta J, Broman JE, Darwish M, et al. Psychomotor effects of zaleplon and thioridazine coadministration. Eur J Clin Pharmacol 2000; 56(3): 211–7PubMedCrossRefGoogle Scholar
  97. 97.
    Sanchez Garcia P, Paty I, Leister CA, et al. Effect of zaleplon on digoxin pharmacokinetics and pharmacodynamics. Am J Health Syst Pharm 2000; 57(24): 2267–70PubMedGoogle Scholar
  98. 98.
    Sanchez Garcia P, Carcas A, Zapater P, et al. Absence of an interaction between ibuprofen and zaleplon. Am J Health Syst Pharm 2000; 57(12): 1137–41PubMedGoogle Scholar
  99. 99.
    Allard S, Sainati SM, Roth-Schechter BF. Coadministration of short-term zolpidem with sertraline in healthy women. J Clin Pharmacol 1999; 39(2): 184–91PubMedCrossRefGoogle Scholar
  100. 100.
    Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole. Clin Pharmacol Ther 1998; 64(6): 661–71PubMedCrossRefGoogle Scholar
  101. 101.
    Villikka K, Rivisto KT, Luurila H, et al. Rifampin reduces plasma concentrations and effects of zolpidem. Clin Pharmacol Ther 1997; 62(6): 629–34PubMedCrossRefGoogle Scholar
  102. 102.
    Hulhoven R, Desager JP, Harvengt C, et al. Lack of interaction between zolpidem and H2 antagonists, cimetidine and ranitidine. Int J Clin Pharmacol Res 1988; 8(6): 471–6PubMedGoogle Scholar
  103. 103.
    Villikka K, Rivisto KT, Lamberg TS, et al. Concentrations and effects of zopiclone are greatly reduced by rifampicin. Br J Clin Pharmacol 1997; 43(5): 471–4PubMedCrossRefGoogle Scholar
  104. 104.
    Jalava KM, Olkkola KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zopiclone. Eur J Clin Pharmacol 1996; 51(3-4): 331–4PubMedCrossRefGoogle Scholar
  105. 105.
    Aranko K, Luurila H, Backman JT, et al. The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone. Br J Clin Pharmacol 1994; 38(4): 363–7PubMedCrossRefGoogle Scholar
  106. 106.
    Alderman CP, Gebauer MG, Gilbert AL, et al. Possible interaction of zopiclone and nefazodone. Ann Pharmacother 2001; 35(11): 1378–80PubMedCrossRefGoogle Scholar
  107. 107.
    Beal S, Sheiner L. NONMEM user guide. San Francisco (CA): University of California, San Francisco, 1998Google Scholar
  108. 108.
    Patat A, Paty I, Hindmarch I. Pharmacodynamic profile of zaleplon, a new non-benzodiazepine hypnotic agent. Hum Psychopharmacol 2001; 16(5): 369–92PubMedCrossRefGoogle Scholar
  109. 109.
    Sanger DJ, Benavides J, Perrault G, et al. Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes. Neurosci Biobehav Rev 1994; 18(3): 355–72PubMedCrossRefGoogle Scholar
  110. 110.
    Sanna E, Busonero F, Talani G, et al. Comparison of the effects of zaleplon, zolpidem, and triazolam at various GABAA receptor subtypes. Eur J Pharmacol 2002; 451(2): 103–10PubMedCrossRefGoogle Scholar
  111. 111.
    Stanski DR, Ham J, Miller RD, et al. Pharmacokinetics and pharmacodynamics of d-tubocurarine during nitrous oxidenarcotic and halothane anesthesia in man. Anesthesiology 1979; 51(3): 235–41PubMedCrossRefGoogle Scholar
  112. 112.
    Sheiner LB, Stanski DR, Vozeh S, et al. Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther 1979; 25(3): 358–71PubMedGoogle Scholar
  113. 113.
    Wada DR, Drover DR, Lemmens HJ. Determination of the distribution volume that can be used to calculate the intravenous loading dose. Clin Pharmacokinet 1998; 35(1): 1–7PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.Department of AnesthesiaStanford University School of MedicineStanfordUSA

Personalised recommendations