Pharmacokinetic properties of zolpidem in elderly and young adults: possible modulation by testosterone in men

Olubodun, J.; Ochs, Hermann R.; Moltke, Lisa L. von; Roubenoff, Ronenn; Hesse, Leah M.; Harmatz, Jerold S.; Shader, Richard I.; Greenblatt, David J.

doi:10.1046/j.0306-5251.2003.01852.x

Cited by 95 publications

(102 citation statements)

References 41 publications

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“…Samples (ϳ1 ml; n ϭ 10 for young and intermediate, n ϭ 7 for old) were evaluated for free testosterone concentrations by immunoassay (Olubodun et al, 2003).…”

Section: Plasma Concentrations Of Testosteronementioning

confidence: 99%

Age-Related Differences in CYP3A Expression and Activity in the Rat Liver, Intestine, and Kidney

Warrington

Greenblatt²,

Moltke³

2004

J Pharmacol Exp Ther

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We evaluated the effect of age on CYP3A expression and function in the liver, intestine, and kidney from young (3-4 months), intermediate (13-14 months), and old (25-26 months) male Fischer-344 rats. The biotransformation of triazolam to its primary hydroxylated products, 4-OH-TRZ (triazolam) and ␣-OH-TRZ, was used as a marker of CYP3A activity in rat liver and intestine. Immunoactive CYP3A expression was evaluated by Western blot analysis in the rat intestine, liver, and kidney. Since testosterone and NADPH reductase levels may modulate CYP3A activity, we also examined free plasma testosterone concentrations and NADPH reductase expression in these rats. The effect of age on CYP3A expression was tissue-specific.Although both CYP3A activity and expression were reduced by approximately 50 to 70% in the old livers compared with the young animals, intestinal CYP3A activity and expression did not change significantly with age. The expression of one CYP3A isoform was increased by 1.5-fold in the old kidneys. NADPH reductase expression was reduced by 23 to 36% with age in all tissues; this reached statistical significance only in the liver. Plasma testosterone levels declined by 74% in the old animals. This study suggests that the effect of age on CYP3A expression and function is tissue-specific. In addition, changes in testosterone levels and NADPH reductase expression may contribute to age-related differences in hepatic CYP3A activity.

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“…Samples (ϳ1 ml; n ϭ 10 for young and intermediate, n ϭ 7 for old) were evaluated for free testosterone concentrations by immunoassay (Olubodun et al, 2003).…”

Section: Plasma Concentrations Of Testosteronementioning

confidence: 99%

Age-Related Differences in CYP3A Expression and Activity in the Rat Liver, Intestine, and Kidney

Warrington

Greenblatt²,

Moltke³

2004

J Pharmacol Exp Ther

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“…It was shown recently that the clearance of zolpidem is substantially diminished in the elderly, particularly in men [18]. Voriconazole is currently used in critically ill patients with extensive fungal infections, and these patients can be very sensitive to the CNS depressant effects of drugs such as zolpidem.…”

Section: Discussionmentioning

confidence: 99%

Effect of voriconazole on the pharmacokinetics and pharmacodynamics of zolpidem in healthy subjects

Saari

Laine

Leino

et al. 2006

Brit J Clinical Pharma

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AimsTo assess the effect of voriconazole on the pharmacokinetics and pharmacodynamics of zolpidem. MethodsIn a randomized cross-over study with two phases, 10 healthy subjects ingested 10 mg of zolpidem with or without oral voriconazole pretreatment. The concentrations of zolpidem were measured in plasma up to 24 h and pharmacodynamic variables were monitored for 12 h. ResultsVoriconazole increased the peak plasma concentration of zolpidem by 1.23-fold [ P < 0.05; 90% confidence interval (CI) 1.05, 1.45] and the area under the plasma zolpidem concentration-time curve by 1.48-fold ( P < 0.001; 90% CI 1.29, 1.74). The time to peak plasma zolpidem concentration was unchanged by voriconazole but the half-life was prolonged from 3.2 to 4.1 h ( P < 0.01; 95% CI on the difference 0.27, 1.45). The pharmacodynamics of zolpidem were unaffected by voriconazole. ConclusionVoriconazole caused a moderate increase in exposure to zolpidem in healthy young subjects but no clear pharmacodynamic changes were observed between the g roups.

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“…Sua eliminação é renal e está reduzida em pacientes com insuficiência renal crônica. A dose terapêutica média para insônia em adultos é de 10mg e de 5mg para idosos 7,8 .…”

Section: Hipnóticos De 2ª Geraçãounclassified

Novos sedativos hipnóticos

Sukys-Claudino

Moraes

Tufik

et al. 2010

Rev. Bras. Psiquiatr.

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ResumoNas últimas décadas houve um esforço para o desenvolvimento de hipnóticos mais seguros e eficazes. Zolpidem, zaleplona, zopiclona, eszopiclona (drogas-z) e indiplona são moduladores do receptor GABA-A, os quais agem de forma seletiva na subunidade α1, exibindo, desta forma, mecanismos similares de ação, embora evidências recentes sugiram que a eszopiclona não seja tão seletiva para a subunidade α1 quanto o zolpidem. Ramelteon e tasimelteon são novos agentes crono-hipnóticos seletivos para os receptores de melatonina MT1 e MT2. Por outro lado, nos últimos anos, o consumo de drogas antidepressivas sedativas tem aumentado significativamente no tratamento da insônia. Como droga experimental, a eplivanserina tem sido testada como um potente agonista inverso do subtipo 5-HT 2A da serotonina, com um uso potencial na dificuldade da manutenção do sono. Outro agente farmacológico para o tratamento da insônia é o almorexant, o qual apresenta um novo mecanismo de ação envolvendo antagonismo do sistema hipocretinérgico, desta forma levando à indução do sono. Finalmente, também discutiremos o potencial papel de outras drogas gabaérgicas no tratamento da insônia.Descritores: Hipnóticos e sedativos; Efeitos fisiológicos de drogas; Receptores de melatonina; Antidepressivos; Distúrbios do início e da manutenção do sono AbstractThere has been a search for more effective and safe hypnotic drugs in the last decades. Zolpidem, zaleplon, zopiclone, eszopiclone (the z-drugs) and indiplon are GABA-A modulators which bind selectively α1 subunits, thus, exhibiting similar mechanisms of action, although recent evidence suggests that eszopiclone is not as selective for α1 subunit as zolpidem is. Ramelteon and tasimelteon are new chrono-hypnotic agents, selective for melatonin MT1 and MT2 receptors. On the other hand, the consumption of sedative antidepressant drugs is significantly increasing for the treatment of insomnia, in the last years. As an experimental drug, eplivanserin is being tested as a potent antagonist of serotonin 2-A receptors (ASTAR) with a potential use in sleep maintenance difficulty. Another recent pharmacological agent for insomnia is almorexant, which new mechanism of action involves antagonism of hypocretinergic system, thus inducing sleep. Finally we also discuss the potential role of other gabaergic drugs for insomnia. Descriptors: Hypnotics and sedatives; Physiological effects of drugs; Receptors, melatonin; Antidepressive agents; Sleep initiation and maintenance disordersIntrodução A insônia é, sem dúvida, na atualidade, o distúrbio do sono mais comum, afetando de 10 a 50% da população 1,2 . As conclusões de um consenso do National Institutes of Health (NHI) indicam que quando utilizamos como critério diagnóstico a necessidade de comprometimento ou impacto nas atividades diurnas, a prevalência da insônia cai para cerca de 10% 3 . Estima-se que cerca de 40% dos indivíduos insones apresentem comorbidade psiquiátrica 4 .Desde a década de 50, a psicofarmacologia vem evoluindo no tratamento da insônia em busca ...

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Pharmacokinetic properties of zolpidem in elderly and young adults: possible modulation by testosterone in men

Cited by 95 publications

References 41 publications

Age-Related Differences in CYP3A Expression and Activity in the Rat Liver, Intestine, and Kidney

Age-Related Differences in CYP3A Expression and Activity in the Rat Liver, Intestine, and Kidney

Effect of voriconazole on the pharmacokinetics and pharmacodynamics of zolpidem in healthy subjects

Novos sedativos hipnóticos

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