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Study, Sep/22: Associ'n bet. CYP2C19 & CYP2B6 phenotypes and safety of diazepam


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The full title of this Spanish study is "Association between CYP2C19 and CYP2B6 phenotypes and the pharmacokinetics and safety of diazepam".

 

https://pubmed.ncbi.nlm.nih.gov/36162369/

 

Abstract

 

Diazepam is a benzodiazepine (BZD) used worldwide for a variety of conditions. Long-term use of diazepam increases the risk for developing tolerance and dependence and for the occurrence of adverse drug reactions (ADRs). CYP3A4 and CYP2C19 mainly metabolize diazepam and are therefore the primary pharmacogenetic candidate biomarkers. In this work, we aimed to explore the impact of CYP3A4 and CYP2C19 phenotypes and of 99 additional variants in other 31 pharmacogenes (including other CYP, UGT, NAT2 and CES enzymes, ABC and SLC transporters) on diazepam pharmacokinetic variability and safety. 30 healthy volunteers that had participated in a single-dose bioequivalence clinical trial of two diazepam formulations were enrolled in the present candidate gene pharmacogenetic study. CYP2C19 poor metabolizers (PMs) showed an almost 2-fold increase in AUC0-∞/DW compared to rapid (RMs) or normal (NM) metabolizers, and a 1.46-fold increase compared to intermediate metabolizers (IMs). CYP2B6 PMs showed a 2,74-fold higher AUC0-∞/DW compared to RMs, and 2.10-fold compared to NMs (p < 0.007). A dose reduction of 25-50 % may be appropriate for CYP2C19 or CYP2B6 PMs to avoid ADRs, dependence and tolerance. Combined CYP2C19 +CYP2B6 PMs may not use diazepam or sharper dose adjustments (e.g., a dose reduction of 50-70 %) may be advisable. To our knowledge, this is the first work to report a strong relationship between CYP2B6 phenotype and diazepam pharmacokinetics. Additional nominal associations (i.e., 0.007 <p < 0.05) between ABCG2, ABCB1, NAT2 and UGT1A4 polymorphisms and pharmacokinetic variability were observed; further research should elaborate on the clinical relevance of the described associations.

 

Keywords: CYP2B6; CYP2C19; Diazepam; Pharmacogenetics.

 

Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

 

Conflict of interest statement

 

Conflict of Interest Statement Dolores Ochoa, Manuel Román and Francisco Abad-Santos have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Cinfa, FAES Farma, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Italfarmaco, Janssen-Cilag, Kern Pharma, Normon, Novartis, Servier, Silverpharma, Teva and Zambon. The remaining authors declare no conflicts of interest.

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I think the importance of the CYP450 enzymes is completely glossed over when it comes to prescribing.

 

I'd have to pay hundreds of dollars to get the DNA tests that could show what my individual profile is, but had I known about all of this information before, it may have saved me from years of pain. Do any doctors pay attention to these genetic differences in the way people metabolize medications? I only learned about it after stumbling upon it as I was reading studies about benzodiazepines and antidepressants.

 

We're not all the same, and we don't all metabolize medications in the same way. I wish I'd known. And I wish my doctors had known.

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