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Pharmacokinetic determinants of clinical activity
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
Given that Nl-dealkylation is a major metabolic pathway for benzodiazepines, and that many clinically important benzodiazepines are N1-substituted, exposure to circulating N-dealkyl metabolites is high. This has important clinical implications, since these metabolites are both biologically active and slowly eliminated from the organism. One such metabolite is desmethyldiazepam. This is produced from many benzodiazepines, most importantly diazepam, but also halazepam, prazepam, oxazolam and others. Indeed, desmethyldiazepam (or nordazepam) is marketed as an anxiolytic in its own right in a number of countries, including Germany. Desmethyldiazepam probably contributes significantly to the biological activity of diazepam and other precursors, particularly after chronic administration, and at later times after single administration. The pharmacokinetic profiles of diazepam and desmethyldiazepam after single administration are illustrated in Figure 7.7. It can be seen that plasma levels of the metabolite actually overtake those of the parent drug during the second day after administration, and remain elevated for over a week, when all traces of diazepam in the organism have essentially disappeared. Desmethyldiazepam is itself slowly metabolised to oxazepam, which is then, as we have seen, rapidly removed from the organism by glucuronoconjugation and renal excretion.
Anxiolytics: Predicting Response/Maximizing Efficacy
Published in Mark S. Gold, R. Bruce Lydiard, John S. Carman, Advances in Psychopharmacology: Predicting and Improving Treatment Response, 2018
Steady-state plasma levels are reached in about 3 days for short half-life and about 2 weeks for long half-life benzodiazepines.244–246 Short half-life benzodiazepines, e.g., oxazepam, lorazepam, and alprazolam, are conjugated to form glucuronides and eliminated in the urine. Their elimination half-lives are in the 5- to 15-hr range, and they must be administered in divided doses. Long half-life benzodiazepines are metabolized to desmethyldiazepam by microsomal enzymes, e.g., diazepam, clorazepate, prazepam, and halazepam. Desmethyldiazepam is an active benzodiazepine with a 36- to 200-hr half-life (see Figure 9). These are effectively given in once-a-day dosing schedules, and are unlikely to produce rebound anxiety if doses are skipped.246 The role of the liver in catabolism of benzodiazepines is clinically significant in patients with liver failure or in the elderly because half-lives are prolonged and doses must be adjusted downward.247,248 Anti-acids are known to reduce clorazepate absorption from the gut by interfering with hydrolysis to desmethyl-diazepam.249,250 Drugs which compete for microsomal enzymes may similarly increase benzodiazepine half-life, e.g., ETOH, cimetadine, etc.251,252 Care must be taken in the intravenous administration of benzodiazepines that the dose is given slowly (2 mg diazepam per minute) because respiratory arrest does sometimes occur.253
Barbiturate and Nonbarbiturate Sedative Hypnotic Intoxication
Published in Sam Kacew, Drug Toxicity and Metabolism in Pediatrics, 1990
S. Bertino Joseph, Michael D. Reed
The various benzodiazepine analogues vary widely in their pharmacokinetic properties. Following oral administration, they are well absorbed from the gastrointestinal (GI) tract. Clorazepate dipotassium is rapidly decarboxylated in the GI tract and absorbed primarily as desmethyldiazepam (nordiazepam, the active metabolite of diazepam). In contrast, chlor-diazepoxide and oxazepam may take several hours for complete absorption to occur, thus delaying the time of the peak serum concentration. Flurazepam and prazepam undergo significant hepatic first pass metabolism, forming active metabolites. The presence of stomach contents or a decrease in gastric emptying time may significantly reduce or delay the absorption of benzodiazepines. When administered via the intramuscular route, water-soluble agents such as midazolam and lorazepam are completely and rapidly absorbed, while water-insoluble agents such as diazepam and chlorodiazepoxide may be erratically and slowly absorbed.
Occurrence and time course of NPS benzodiazepines in Sweden – results from intoxication cases in the STRIDA project
Published in Clinical Toxicology, 2019
Matilda Bäckberg, Madeleine Pettersson Bergstrand, Olof Beck, Anders Helander
The NPS BZD covered in this study (Figure 2) were adinazolam, bentazepam, clonazolam, cloniprazepam, diclazepam, deschloroetizolam, flubromazolam, flunitrazolam, 3-hydroxyflubromazepam, ketazolam, meclonazepam, metizolam, nifoxipam, nitrazolam, pivoxazepam, and pyrazolam (1 mg/mL solutions from Chiron, Trondheim, Norway), bromazepam, clobazam, etizolam, estazolam, flurazepam, 3-hydroxyphenazepam, N-desmethylflunitrazepam, nimetazepam, phenazepam, and prazepam (1 mg/mL solutions from Cerilliant, Round Rock, TX), flubromazepam (1 mg/mL solution from LGC, Teddington, UK), and tetrazepam (0.1 mg/mL solution from LGC). All solutes were obtained in acetonitrile or methanol.
Enzalutamide and analytical interferences in digoxin assays
Published in Clinical Toxicology, 2018
Marie Deguigne, Marion Brunet, Chadi Abbara, Alain Turcant, Gaël Le Roux, Bénédicte Lelièvre
Analysis of plasma samples for the second patient was performed using a HPLC-UV/DAD method (HP1100 HPLC system, Agilent technologies, Les Ulis, France), as described in Turcant et al.’s article [11] After adding 25 µL of internal standard at a concentration of 20 mg/L (prazepam) to 500 µL of samples, the preparation was extracted using a liquid–liquid extraction in an alkaline condition. Data acquisition was performed at three different wavelengths (210, 230, and 254 nm) and products were identified by comparing the UV spectra and the retention time of the analyte to those listed in the laboratory’s database of UV spectra “Toxicol.”