Pharmacokinetic determinants of clinical activity
Adam Doble, Ian L Martin, David Nutt in Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
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.
Pharmacological Treatment of Anxiety Disorders Across the Lifespan
Stephen M. Stahl, Bret A. Moore in Anxiety Disorders: A Guide for Integrating Psychopharmacology and Psychotherapy, 2013
The adverse cognitive effects of benzodiazepines are insidious and often missed in clinical practice. The reason for this is the long half-lives of these drugs, almost all of which exceed the usually prescribed dose intervals. For example, several benzodiazepines are metabolized to a long-acting active intermediate (nordiazepam) that has a half-life of several days. Others considered to be shorter-acting have half-lives of 12–14 hours (alprazolam, temazepam, lorazepam) or more than 24 hours (clonazepam). Only triazolam (half-life of 2.5 hours) and midazolam (half-life of about 1.5 hours) have a rapid onset and noticeable cessation of action. When a drug with a half-life of greater than 12 hours is administered every 6–8 hours, one is never “drug-free.” As a result, even professionals seeing these persons rarely notice drug-induced impairments. Even if the benzodiazepine is taken only at bedtime for sleep, residual daytime impairment will persist and some drug remains when the next bedtime dose is taken (leading to drug accumulation and even more impairment).
Coupled Mass Spectrometic—Chromatographic Systems
Steven H. Y. Wong, Iraving Sunshine in Handbook of Analytical Therapeutic Drug Monitoring and Toxicology, 2017
CI has become more widely used in the toxicology community to achieve lower limits of detection. Over 50 papers have appeared in the last 5 years using CI in pharmacokinetic and drug safety studies. The basic chemistry of CI has been reviewed by Harrison.25 The design of the ion source is critical in achieving ultimate limits of detection, and some source designs compromise CI efficiency for simplicity in conversion from EI operation. In these cases, careful optimization of EI conditions can give detection limits similar to PCI caused by the inefficiency of the ionization process. Ishikawa et al.76 found that the EI-SIM limits of detection for phenothiazines in plasma or urine were lower than either PCI or NCI. In general, however, NCI has shown improved detection limits. This seems to be caused by the decrease in background a result of the selective electron capture mechanism that gives rise to the ions observed. Papac and Foltz77 were able to analyze LSD in urine or plasma by GC/NCI/MS after conversion to its N-trifluoroacetyl derivative. A linear response from 0.1 to 3.0 μg/l was observed in plasma. Fitzgerald et al.64 selected NCI for analysis of the TMS derivatives of nordiazepam, oxazepam, temazepam, lorazepam, N-l-hydroxyethylflurazepam, α-hydroxyalprazolam, and α-hydroxytriazolam, because the limits of detection (50 μg/l) were up to several thousand times better than either PCI or EI.
Sentanyl: a comparison of blood fentanyl concentrations and naloxone dosing after non-fatal overdose
Published in Clinical Toxicology, 2022
Alex J. Krotulski, Brittany P. Chapman, Sarah J. Marks, Sam T. Ontiveros, Katharine Devin-Holcombe, Melissa F. Fogarty, Hai Trieu, Barry K. Logan, Roland C. Merchant, Kavita M. Babu
Polydrug use was common. Ten participants’ (50.0%) blood samples showed markers of cocaine use (cocaine, benzoylecgonine, and/or cocaethylene) and methamphetamine use for one participant (5.0%). Buprenorphine (Suboxone®) was detected in one blood specimen (5.0%), while methadone and its metabolite were not found in any specimens. Acetylfentanyl was detected in two blood specimens (10.0%). Carfentanil was detected in the blood of one participant (5.0%). Benzodiazepines were detected in six participants (30.0%); one patient had nordiazepam detected in their specimen. Antidepressants were found in three (15.0%) specimens. Detailed testing results are in Table 2.
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