Biopharmacological data and high-performance liquid chromatographic analysis of 1,4-benzodiazepines in biological fluids: A review

Berrueta, Luis Á.; Gallo, Blanca; Vicente, Francisca

doi:10.1016/0731-7085(92)80019-j

Cited by 46 publications

(13 citation statements)

References 104 publications

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“…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%

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: Identification Of the Main Metabolitesmentioning

confidence: 99%

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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“…They are believed to act on the GABA receptor GABA A , an inhibitory neurotransmitter, the activation of which dampens higher neuronal activity. Though they are relatively safe drugs with mild side effects, in case of overdose they may be fatal [1]. They are frequently encountered in clinical and forensic science casework.…”

Section: Introductionmentioning

confidence: 99%

Development of a validated HPLC method for the determination of four 1,4‐benzodiazepines in human biological fluids

Samanidou

Pechlivanidou

Papadoyannis³

2007

J of Separation Science

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A simple and sensitive HPLC method was developed and validated for the determination of four frequently prescribed 1,4-benzodiazepines: alprazolam (ALP), bromazepam (BRZ), diazepam (DZP), and flunitrazepam (FNZ). Separation was achieved on an Inertsil C8 analytical (250 mm x 4 mm, 5 microm) column, after selective extraction of benzodiazepine drugs from biological matrices by means of SPE. Isocratic elution was performed with a mobile phase consisting of CH3COONH4, 0.05 M CH3OH, and CH3CN (33:57:10 by volume). Quantification was performed at 240 nm with mefenamic acid (6 ng/microL) as the internal standard. DSC-18 Supelco cartridges provided high absolute recoveries (81-115%). The developed method was fully validated in terms of selectivity, linearity, accuracy, precision, stability, and sensitivity. Repeatability (n = 8) and between-day precision (n = 8) revealed RSD <12%. Recoveries from biological samples ranged from 81.2 to 115%. The detection limit of the method was calculated as 3.3-10.2 ng in blood plasma and 2.6-12.6 ng in urine for 20 microL injection volume. The method was applied to spiked biological matrices. Moreover, the method was applied to real samples of urine after an oral administration.

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“…The detector output was recorded using a Shimadzu C-R3A integrator (Shimadzu, Hertogenbosch, The Netherlands). In some cases the analytical procedure was slightly modified (Berrueta et al, 1992). The zopiclone and flunitrazepam plasma samples were diluted with 0.5 ml of 0.2 M borate buffer, pH 8.0, and 0.5 ml of 1 M borate buffer, pH 9.5, respectively.…”

Section: Methodsmentioning

confidence: 99%

Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of the Electroencephalogram Effects of GABA_AReceptor Modulators: In Vitro-in Vivo Correlations

Visser¹,

Wolters²,

Gubbens‐Stibbe³

et al. 2003

J Pharmacol Exp Ther

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A mechanism-based pharmacokinetic-pharmacodynamic (PK/ PD) model for neuroactive steroids, comprising a separate characterization of 1) the receptor activation process and 2) the stimulus-response relationship, was applied to various nonsteroidal GABA A receptor modulators. The EEG effects of nine prototypical GABA A receptor modulators (six benzodiazepines, one imidazopyridine, one cyclopyrrolone, and one ␤-carboline) were determined in rats in conjunction with plasma concentrations. Population PK/PD modeling revealed monophasic concentration-EEG effect relationships with large differences in potency (EC 50 ) and intrinsic activity between the compounds. The data were analyzed on the basis of the mechanism-based PK/PD model for (synthetic) neuroactive steroids on the assumption of a single and unique stimulus-response relationship. The model converged yielding estimates of both the apparent in vivo receptor affinity (K PD ) and the in vivo intrinsic efficacy (e PD ). The values of K PD ranged from 0.41 Ϯ 0 ng⅐ml Ϫ1 for bretazenil to 436 Ϯ 72 ng⅐ml Ϫ1 for clobazam and the values for e PD from Ϫ0.27 Ϯ 0 for methyl 6,7-dimethoxy-4-ethyl-␤-carboline-3-carboxylate to 0.54 Ϯ 0.02 for diazepam. Significant linear correlations were observed between K PD for unbound concentrations and the affinity in an in vitro receptor bioassay (r ϭ 0.93) and between e PD and the GABA-shift in vitro (r ϭ 0.95). The findings of this investigation show that the in vivo effects of nonsteroidal GABA A receptor modulators and (synthetic) neuroactive steroids can be described on the basis of a single unique transducer function. In this paradigm, the nonsteroidal GABA A receptor modulators behave as partial agonists relative to neuroactive steroids.The pharmacokinetic-pharmacodynamic correlations of benzodiazepines have been the subject of numerous studies in both animals and humans for review, see Laurijssens and Greenblatt, 1996), but the predictive value of the proposed models seems to be limited. To date, there is an increasing interest in the development of mechanism-based PK/PD models because they allow the prediction of drug effects in vivo in a strict, quantitative manner on the basis of results obtained in in vitro test systems. These models not only provide a scientific basis for the prediction of drug effects in humans on the basis of results obtained in animal studies but also allow a mechanistic understanding for observed interindividual variability in drug response (Van der Graaf and Danhof, 1997).The need for mechanism-based modeling is illustrated by the difficulty of predicting the in vivo intrinsic activity of benzodiazepine receptor partial agonists in humans on the basis of results obtained in preclinical investigations. For example, in humans, the new benzodiazepine Ro 46-2153 behaved as a full agonist, whereas it was selected from preclinical studies based on its partial agonist properties (Goggin et al., 2000).In mechanism-based PK/PD models that are based on receptor theory, a separation is made between th...

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Biopharmacological data and high-performance liquid chromatographic analysis of 1,4-benzodiazepines in biological fluids: A review

Cited by 46 publications

References 104 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

Development of a validated HPLC method for the determination of four 1,4‐benzodiazepines in human biological fluids

Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of the Electroencephalogram Effects of GABA_AReceptor Modulators: In Vitro-in Vivo Correlations

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Biopharmacological data and high-performance liquid chromatographic analysis of 1,4-benzodiazepines in biological fluids: A review

Cited by 46 publications

References 104 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

Development of a validated HPLC method for the determination of four 1,4‐benzodiazepines in human biological fluids

Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of the Electroencephalogram Effects of GABAAReceptor Modulators: In Vitro-in Vivo Correlations

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Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of the Electroencephalogram Effects of GABA_AReceptor Modulators: In Vitro-in Vivo Correlations