WE READ WITH interest the paper by Huang et al., addressing the issue of zolpidem abuse, dependence and withdrawal syndrome.1 They described an interesting case of dependence on ultrahigh dose of zolpidem and withdrawal seizure, emphasizing the risk of abuse.

The Huang et al. core hypothesis for the phenomena described in the case report on a female patient is that zolpidem at high doses might lose its selectivity for γ-aminobutyric acid-A receptor and exhibit the same pharmacologic effects as classic benzodiazepines.1 Because zolpidem dependence and the related seizures were previously seen in subjects taking 160–600 mg/day2 and Huang et al. report on a patient who had taken 2000 mg per day,1 the pharmacodynamics is of vital interest. However, my impression of that interesting paper was that Dr Huang and coworkers had not addressed the important issues of pharmacokinetics and sex of the patient and, because the pharmacodynamic issues are discussed in a conclusive way, the pharmacokinetics seems to be underrepresented. Most of the zolpidem-related disorders involved female patients because women achieve up to 50% higher zolpidem plasma levels3 and sex-related differences in zolpidem clearance are significant.4 Zolpidem metabolism is mediated by human cytochromes P450 (CYP), with CYP3A4 reported as having a dominant role based on the contributory role of CYP1A2, 2C9 and 2D6, but not of 2A6, 2E1, and 2C8.5 Thus the pharmacokinetic interactions may occur in patients receiving analgesics, anti-arrhythmics, antibiotics, antiepileptics, antihistamines, anti-neoplasm, antiparkinsonian drugs, anti-progesterone agents, anti-rejection drugs, beta-blockers, calcium-channel blockers, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, proton pump inhibitors, steroids, or triptans. Zolpidem is hepatically metabolized and its plasma protein binding is markedly decreased in the presence of hepatic impairment, which might have contributed to the occurrence of the seizure in women due to contraception.6 Also, plasma protein binding of zolpidem is decreased in the presence of renal insufficiency.7

In many cases, pharmacokinetics contributes equally as pharmacodynamics to the observed adverse drug reactions. With regard to the emerging issues in zolpidem abuse, the evidence that the consideration of pharmacokinetics can improve zolpidem pharmacotherapy with regard to efficacy and safety is of vital importance.


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  • 1
    Huang MC, Lin HY, Chen CH. Dependence on zolpidem. Psychiatry Clin. Neurosci. 2007; 61: 207208.
  • 2
    Cubala WJ, Landowski J. Seizure following sudden zolpidem withdrawal. Prog. Neuropsychopharmacol. Biol. Psychiatry 2007; 31: 539540.
  • 3
    Tripodianakis J, Potagas C, Papageorgiou P, Lazaridou M, Matikas N. Zolpidem-related epileptic seizures: A case report. Eur. Psychiatry 2003; 18: 140141.
  • 4
    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: 435443.
  • 5
    Von Moltke LL, Greenblatt DJ, Granda BW et al. Zolpidem metabolism in vitro: Responsible cytochromes, chemical inhibitors, and in vivo correlations. Br. J. Clin. Pharmacol. 1999; 48: 8997.
  • 6
    Olubodun JO, Ochs HR, Trüten V et al. Zolpidem pharmacokinetic properties in young females: Influence of smoking and oral contraceptive use. J. Clin. Pharmacol. 2002; 42: 11421146.
  • 7
    Pacifici GM, Viani A, Rizzo G et al. Plasma protein binding of zolpidem in liver and renal insufficiency. Int. J. Pharmacol. Ther. Toxicol. 1988; 26: 439443.