Benzodiazepine metabolites

Koch TR, Raglin RL, Kirk S, Bruni JF. Improved screening for benzodiazepine metabolites in urine using the Triage panel for drugs of abuse. J Anal Toxicol 1994 18 168-72. 

Fraser, A.D. Urinary screening for alprazolam, triazolam, and their metabolites with the EMIT d.a.u. benzodiazepine metabolite assay. J.Anal.ToxicoL, 1987, 11, 263—266... 

HPTLC. Moreover, UTLC provides faster separations and lower solvent consnmption and allows detecting analytes at the picomole range. In addition, Solo s group studied the feasibiUty of UTLC-AP-MALDI-MS for trioassays using benzodiazepines as model substances in human urine [45], The separation efficiency of benzodiazepines was studied using ID UTLC and 2D UTLC. Between two TLC methods, 2D UTLC was shown to be an efficient technique for the separation of benzodiazepines. This method provides LOD within the picomole range for benzodiazepine metabolites in an authentic urine sample. 

Benzodiazepine enantiomers have also been resolved on the Chiralcel OD CSP. Wang et al. utilized this CSP to determine the enantiomeric composition of camazepam and its metabolites [59]. SFC provided improved resolution of the compounds of interest in a shorter period of time than LC. Phinney et al. demonstrated the separation of a series of achiral and chiral benzodiazepines. An amino column was coupled in series with the Chiralcel OD CSP to achieve the desired separation [41]. 

Finally, the presence in human post-mortem brain tissue of the active metabolite of diazepam, desmethyldiazepam, raised some curiosity and frank alarm (Sangameswaran et al. 1986). At the time of its discovery in the brain it was thought that there was no enzyme system capable of producing such halogenated compounds and that its presence in the brain reflected dietary intake from an environment contaminated by overuse of its parent compound. However, its discovery in stored brain tissue which had been obtained before the synthesis of the benzodiazepines allayed these fears. It is now thought possible that some benzodiazepines, including desmethyldiazepam, occur naturally and that they are taken in as part of a normal diet (Table 19.5). 

Applications APCI-MS is often more widely applicable than ESI-MS to the analysis of classes of compounds with a low molecular weight, such as basic drugs and their metabolites, antibiotics, steroids, oestrogens, benzodiazepines, pesticides, surfactants, and most other organic compounds amenable to El. LC-APCI-MS has been used to analyse PET extracts obtained by a disso-lution/precipitation procedure [147]. Other applications of hyphenated APCI mass spectrometric techniques are described elsewhere LC-APCI-MS (Section 7.33.2) and packed column SFC-APCI-MS (Section 73.2.2) for polar nonvolatile organics. 

Numerous neurotransmitter receptors are located in the vomiting center, CTZ, and GI tract. Examples of such receptors include cholinergic and histaminic, dopaminergic, opiate, serotonin, neurokinin (NK), and benzodiazepine receptors. Theoretically, chemotherapeutic agents, their metabolites, or other emetic compounds trigger the process of emesis through stimulation of one or more of these receptors. 

Zolpidem, chemically unrelated to benzodiazepines or barbiturates, acts selectively at the y-aminobutyric acidA (GABAA)-receptor and has minimal anxiolytic and no muscle relaxant or anticonvulsant effects. It is comparable in effectiveness to benzodiazepine hypnotics, and it has little effect on sleep stages. Its duration is approximately 6 to 8 hours, and it is metabolized to inactive metabolites. Common side effects are drowsiness, amnesia, dizziness, headache, and GI complaints. Rebound effects when discontinued and tolerance with prolonged use are minimal, but theoretical concerns about abuse exist. It appears to have minimal effects on next-day psychomotor performance. The usual dose is 10 mg (5 mg in the elderly or those with liver impairment), which can be increased up to 20 mg nightly. Cases of psychotic reactions and sleep-eating have been reported. 

Diazepam and its nordiazepam, oxazepam, and temazepam metabolites are well retained by the MIP, while they are much less retained on NIP, also exhibiting large RSD. Other benzodiazepines of similar structures (Figure 1.50) were well retained on the MIP, showing that this template can be used for the general class of benzodiazepines. Two benzodiazepines studied, chlordiazepoxide and flunitrazepam, were poorly retained, indicating poor fit of these structures into the templated MIP. 

Hydrolytic cleavage of a seven-membered ring occurs in the metabolism of chlordiazepoxide (5.82, Fig. 5.22,a) and other benzodiazepines (see also Sect. 11.9). The lactam ring opened metabolite 5.83 was detected in humans and dogs and is believed to be generated by hydrolysis of the intermediate lactam [181][182], However, the diazepine ring can be split by other mech-... 

Miki A, Tatsuno M, Katagi M, Nishikawa M, Tsuchihashi H. 2002. Simultaneous determination of eleven benzodiazepine hypnotics and eleven relevant metabolites in urine by column-switching liquid chromatography-mass spectrometry. J Anal Toxicol 26 87. 

Toyo oka T, Kumaki Y, Kanbori M, Kato M, Nakahara Y. 2003. Determination of hypnotic benzodiazepines (alprazolam, estrazolam, and midazolam) and their metabolites in rat hair and plasma by reversed-phase liquid-chromatography with electrospray ionization mass spectrometry. J Pharm Biomed Anal 30 1773. 

In the presence of cirrhosis or other liver impairment, lorazepam or oxazepam should be utilized for detoxification. These two benzodiazepines have no active hepatic metabolites and are generally considered safer choices for patients with liver damage. Once the starting point for the taper is determined, the dose is decreased by 10-20% per day. It is important to note that this rate of taper is much faster than that used for patients treated chronically with benzodiazepines who are discontinuing their anxiolytic in order to determine if it is still needed for control of symptoms. In that case, the rate of decrease is 10-20% per week. Should the patient display... 

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