Plasma levels of chlorodesmethyldiazepam in humans

Bo, Lorenzo Dal; Marcucci, F.; Mussini, E.; Perbellini, D; Castellani, A.; Fresia, Pablo

doi:10.1002/bdd.2510010306

Cited by 7 publications

(8 citation statements)

References 9 publications

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“…All three main metabolites of diclazepam are pharmacologically active with elimination half-lives of 78 h (delorazepam), [11] 12 h (lorazepam) [16] and 13 h (lormetazepam), [17] respectively. All three main metabolites of diclazepam are pharmacologically active with elimination half-lives of 78 h (delorazepam), [11] 12 h (lorazepam) [16] and 13 h (lormetazepam), [17] respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Diclazepam shows a rather long terminal elimination half-life of approximately 42 h and its pharmacokinetic profile seems to follow a multi-compartment model showing at least biphasic elimination. All three main metabolites of diclazepam are pharmacologically active with elimination half-lives of 78 h (delorazepam), [11] 12 h (lorazepam) [16] and 13 h (lormetazepam), [17] respectively. As a consequence, long-lasting sedative effects seem likely when applying higher or repeated doses.…”

Section: Resultsmentioning

confidence: 99%

“…In case of the EPI experiments hypothetic masses of potential phase I metabolites including mono-, di-and trihydroxylation, demethylation, dehalogenation, methoxylation, formation of an aminobenzophenone or quinazoline-2-one as well as combinations and potential phase II metabolites (glucuronidation or sulfation) of the above, reflecting common metabolic steps for benzodiazepines, [9][10][11][12] were implied. In case of the EPI experiments hypothetic masses of potential phase I metabolites including mono-, di-and trihydroxylation, demethylation, dehalogenation, methoxylation, formation of an aminobenzophenone or quinazoline-2-one as well as combinations and potential phase II metabolites (glucuronidation or sulfation) of the above, reflecting common metabolic steps for benzodiazepines, [9][10][11][12] were implied.…”

Section: Identification Of the Main Metabolitesmentioning

confidence: 99%

“…In case of the EPI experiments hypothetic masses of potential phase I Drug Test. Analysis 2014, 6, 757-763 metabolites including mono-, di-and trihydroxylation, demethylation, dehalogenation, methoxylation, formation of an aminobenzophenone or quinazoline-2-one as well as combinations and potential phase II metabolites (glucuronidation or sulfation) of the above, reflecting common metabolic steps for benzodiazepines, [9][10][11][12] were implied. For precursor ion experiments characteristic fragments of delorazepm, diclazepam, lorazepam and lormetazepam were included as precursor masses.…”

Section: Identification Of the Main Metabolitesmentioning

confidence: 99%

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Characterization of the designer benzodiazepine diclazepam and preliminary data on its metabolism and pharmacokinetics

Moosmann

Bisel

Auwärter

2014

Drug Testing and Analysis

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Designer benzodiazepines, first offered in online shops selling 'research chemicals' in 2012, provide an attractive alternative to prescription-only benzodiazepines as they are readily available over the Internet at a low price. However, as data regarding pharmacokinetic parameters, metabolism, and detectability in biological fluids are limited, they present a challenge for forensic laboratories. Most recently, diclazepam (other names: 2-chlorodiazepam, Ro 5-3448 or 7-chloro-5-(2-chlorophenyl)-1-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one) emerged as a new compound in this class of drugs. In this paper, this new designer benzodiazepine was characterized utilizing nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS) as well as liquid chromatography tandem mass spectrometry (LC-MS/MS) techniques. Furthermore, a self-experiment was performed to gain preliminary data on pharmacokinetic properties and to identify the main metabolites. For this purpose, one tablet of diclazepam (declared amount: 1 mg) was ingested by one of the authors, and serum as well as urine samples were collected for 14 and 21 days, respectively. Based on this study, diclazepam has an approximate elimination half-life of 42 h and is metabolized into the pharmacologically active benzodiazepines delorazepam, lorazepam, and lormetazepam which can be detected in urine for 6, 19, and 11 days, respectively, when applying the presented LC-MS/MS method. In serum, the consumption could be proven between 99 h post-intake targeting the parent compound and up to 10 days targeting the metabolite delorazepam. As immunochemical assays are applied for screening purposes quite often, detectability using this technique was assessed, especially since detection of low-dosed benzodiazepines can be sometimes problematic. However, only one of the utilized immunochemical assays was capable of detecting the intake of one tablet diclazepam, and the positive results were restricted to a few urine samples showing relatively high creatinine concentrations.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Identification Of the Main Metabolitesmentioning

confidence: 99%

Section: Identification Of the Main Metabolitesmentioning

confidence: 99%

See 2 more Smart Citations

Characterization of the designer benzodiazepine diclazepam and preliminary data on its metabolism and pharmacokinetics

Moosmann

Bisel

Auwärter

2014

Drug Testing and Analysis

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“…Preliminary pharmacokinetic studies indicated that CDDZ has a rather long half-life (5). It has also been shown that in mice, rats, dogs and humans the most important active metabolite of CDDZ is its hydroxylated derivative, Lorazepam (LRZ) (6)(7)(8).…”

Section: Introduction Subjects and Methodsmentioning

confidence: 99%

Pharmacokinetics of chlordesmethyldiazepam after single-dose oral administration in humans

Bareggi¹,

Pirola²,

Leva³

et al. 1986

European Journal of Drug Metabolism and Pharmacokinetics

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The pharmacokinetics of chlordemethyldiazepam--a pharmacologically very active new 1,4-benzodiazepine derivative--in healthy subjects after administration of a single oral dose of 2 mg, was studied. Peak concentrations were reached in 1.2 +/- 0.2 hours. Plasma levels declined with a biphasic pattern, and the elimination phase had a half-life of 82.9 +/- 14.1 hours. The concentrations of the main metabolite of chlordemethyldiazepam, lorazepam, were about 7% of those of the parent compound. In urine only conjugated lorazepam could be found its 96 hour excretion reaching about 15% of the administered dose of parent drug.

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Quantification of chlordesmethyldiazepam by liquid chromatography–tandem mass spectrometry: application to a cloxazolam bioequivalence study

Oliveira‐Silva

Oliveira

Mendes

et al. 2009

Biomedical Chromatography

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A rapid, sensitive and specific LC-MS/MS method was developed and validated for quantifying chlordesmethyldiazepam (CDDZ or delorazepam), the active metabolite of cloxazolam, in human plasma. In the analytical assay, bromazepam (internal standard) and CDDZ were extracted using a liquid-liquid extraction (diethyl-ether/hexane, 80/20, v/v) procedure. The LC-MS/MS method on a RP-C18 column had an overall run time of 5.0 min and was linear (1/x weighted) over the range 0.5-50 ng/mL (R > 0.999). The between-run precision was 8.0% (1.5 ng/mL), 7.6% (9 ng/mL), 7.4% (40 ng/mL), and 10.9% at the low limit of quantification-LLOQ (0.500 ng/mL). The between-run accuracies were 0.1, -1.5, -2.7 and 8.7% for the above mentioned concentrations, respectively. All current bioanalytical method validation requirements (FDA and ANVISA) were achieved and it was applied to the bioequivalence study (Cloxazolam -- test, Eurofarma Lab. Ltda and Olcadil -- reference, Novartis Biociências S/A). The relative bioavailability between both formulations was assessed by calculating individual test/reference ratios for Cmax, AUClast and AUC0-inf. The pharmacokinetic profiles indicated bioequivalence since all ratios were as proposed by FDA and ANVISA.

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Plasma levels of chlorodesmethyldiazepam in humans

Cited by 7 publications

References 9 publications

Characterization of the designer benzodiazepine diclazepam and preliminary data on its metabolism and pharmacokinetics

Characterization of the designer benzodiazepine diclazepam and preliminary data on its metabolism and pharmacokinetics

Pharmacokinetics of chlordesmethyldiazepam after single-dose oral administration in humans

Quantification of chlordesmethyldiazepam by liquid chromatography–tandem mass spectrometry: application to a cloxazolam bioequivalence study

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