Determination of zolpidem and its metabolites by chromatography-mass spectrometry

Крылова, Е. А.; Kataev, S. S.; Khomov, Yu. A.

doi:10.1134/s1061934813080066

Cited by 5 publications

(3 citation statements)

References 5 publications

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“…More recent reports on zolpidem metabolism can be found in references [38, 39]. The six metabolites of 1 , which are shown in Scheme 4, were included in this study.…”

Section: Resultsmentioning

confidence: 99%

Psychiatric Disorders and Oxidative Injury: Antioxidant Effects of Zolpidem Therapy disclosed In Silico

Bortoli

Tiezza

Muraro

et al. 2019

Computational and Structural Biotechnology Journal

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Zolpidem ( N , N -Dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2- a ]pyridin-3-yl]acetamide) is a well-known drug for the treatment of sleeping disorders. Recent literature reports on positive effects of zolpidem therapy on improving renal damage after cisplatin and on reducing akinesia without sleep induction. This has been ascribed to the antioxidant and neuroprotective capacity of this molecule, and tentatively explained according to a generic structural similarity between zolpidem and melatonin. In this work, we investigate in silico the antioxidant potential of zolpidem as scavenger of five ROSs, acting via hydrogen atom transfer (HAT) mechanism; computational methodologies based on density functional theory are employed. For completeness, the analysis is extended to six metabolites. Thermodynamic and kinetic results disclose that indeed zolpidem is an efficient radical scavenger, similarly to melatonin and Trolox, supporting the biomedical evidence that the antioxidant potential of zolpidem therapy may have a beneficial effect against oxidative injury, which is emerging as an important etiopathogenesis in numerous severe diseases, including psychiatric disorders.

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“…More recent reports on zolpidem metabolism can be found in references [38, 39]. The six metabolites of 1 , which are shown in Scheme 4, were included in this study.…”

Section: Resultsmentioning

confidence: 99%

Psychiatric Disorders and Oxidative Injury: Antioxidant Effects of Zolpidem Therapy disclosed In Silico

Bortoli

Tiezza

Muraro

et al. 2019

Computational and Structural Biotechnology Journal

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“…It is subjected to extensive hepatic metabolism, and although zolpidem is a substrate to several distinct CYP450 isoenzymes, its major metabolic pathway is mediated by CYP3A4 (61%); to a lesser extent, this drug is metabolized by other CYP isoforms such as: 2C9 (22%), 1A2 (14%), 2C19 and 2D6 (< 3%) [36]. Zolpidem is converted via oxidation and hydroxylation to three pharmacologically inactive metabolites, of which the 4-carboxy-derivative is the predominant one (zolpidem phenyl-4-carboxylic acid; Z4CA), representing 72% up to 86% of the administered dose [18,28]. Bupropion is an antidepressant whose mechanism of action includes the inhibition of both norepinephrine and dopamine reuptake [1,16].…”

Section: Introductionmentioning

confidence: 99%

Assessment of the Effects of Steady-State Bupropion on the Pharmacokinetic Profile of Zolpidem in Healthy Volunteers

Gheldiu¹

2019

FARMACIA

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The study's purpose was to evaluate if bupropion, an antidepressant agent, can influence the pharmacokinetic profile of zolpidem, a sedative/hypnotic drug, and its main metabolite (zolpidem phenyl-4-carboxylic acid, Z4CA). The open-label, non-randomized, sequential clinical trial consisted of two periods: Period 1, when each volunteer received a single dose of zolpidem 5 mg and Period 2, when a combination of zolpidem 5 mg and bupropion 300 mg was administered, after a 7-day pre-treatment with bupropion. Pharmacokinetic analysis used for the non-compartmental approach and safety evaluations were conducted during the study. Bupropion pre-treatment decreased mean C max and AUC 0-∞ for zolpidem and increased the same parameters for Z4CA. Most of zolpidem's pharmacokinetic parameters displayed statistically significant differences between study periods. These results demonstrated that a pharmacokinetic interaction does occur between these drugs, possibly due to CYP3A4 induction, hypothesis which needs to be further investigated. RezumatScopul studiului a fost de a evalua dacă bupropiona, un antidepresiv, poate influența profilul farmacocinetic al zolpidemului, un sedativ/hipnotic, și al principalului său metabolit (zolpidem acid fenil-4-carboxilic, Z4CA). Studiul clinic deschis, nonrandomizat, secvențial a constat în două perioade: Perioada 1, când fiecare voluntar a primit o doză unică de zolpidem 5 mg și Perioada 2, când s-au co-administrat zolpidem 5 mg și bupropionă 300 mg, după 7 zile de pre-tratament cu bupropionă. Analiza farmacocinetică a utilizat metoda non-compartimentală, iar în timpul studiului s-a urmărit și evaluarea siguranței terapiei. Pre-tratamentul cu bupropionă a scăzut valoarea medie a C max și AUC 0-∞ pentru zolpidem și a crescut aceiași parametri pentru Z4CA. Majoritatea parametrilor farmacocinetici ai zolpidemului au prezentat diferențe semnificative statistic între perioadele de studiu. Aceste rezultate au demonstrat că există o interacțiune farmacocinetică între aceste medicamente, posibil datorită inducției CYP3A4, ipoteză care trebuie investigată în continuare.

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“…Zolpidem is a substrate to several distinct CYP 450 isoenzymes, among which the major metabolism pathway occurs through CYP3A4 (61%) [9,10,11]. It is converted to three pharmacologically inactive metabolites in the liver via oxidation and hydroxylation, of which the 4-carboxy-derivative is the predominant one (zolpidem phenyl-4-carboxylic acid -Z4CA), representing 72 up to 86% of the administered dose [12,13,14]. The time to reach the maximum plasma concentration is around 0.5-3 hr and the half-life time of zolpidem is about 2-3 hours [3,4].…”

Section: Introductionmentioning

confidence: 99%

Kinetics of Zolpidem and Its Metabolite after Single Dose Oral Administration

Gheldiu¹,

Csavdari²,

Achim³

et al. 2017

Studia UBB Chemia

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ABSTRACT. The present study aimed to describe the basic pharmacokinetics of zolpidem and its metabolite zolpidem phenyl-4-carboxylic acid after a single oral dose of 5 mg zolpidem. Six competing kinetic models were created in order to analyze the experimental data obtained from the 20 healthy volunteers enrolled in a clinical study. Based on rational model discrimination criteria (Akaike index value), the best one was chosen and further used for a better understanding of the kinetics of zolpidem and its metabolite in the body after administration. The kinetic model considers that zolpidem absorption process follows a first-order kinetics and during this stage it is partially metabolized (pre-systemic metabolism) to its main metabolite. The kinetics of both zolpidem and its metabolite is characterized by bicompartmental distribution and first order kinetics of both elimination and systemic metabolism.

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Determination of zolpidem and its metabolites by chromatography-mass spectrometry

Cited by 5 publications

References 5 publications

Psychiatric Disorders and Oxidative Injury: Antioxidant Effects of Zolpidem Therapy disclosed In Silico

Psychiatric Disorders and Oxidative Injury: Antioxidant Effects of Zolpidem Therapy disclosed In Silico

Assessment of the Effects of Steady-State Bupropion on the Pharmacokinetic Profile of Zolpidem in Healthy Volunteers

Kinetics of Zolpidem and Its Metabolite after Single Dose Oral Administration

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