Using the CYP3A Activity Evaluation to Predict the Efficacy and Safety of Diazepam in Patients With Alcohol Withdrawal Syndrome

Abstract

Background:

Diazepam is one of the most commonly prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS). Despite its popularity, there is currently no precise information on the effect of genetic polymorphisms on the efficacy and safety of diazepam therapy.

Objective:

The objective of our study was to study the effect of CYP3A isoenzymes activity on the efficacy and safety of diazepam in patients with AWS.

Methods:

The study was conducted on 30 Russian male patients suffering from the AWS who received diazepam in injections at a dosage of 30.0 mg / day for 5 days. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions.

Results:

Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP3A4 C>T intron 6 (rs35599367) genotypes: (CC) −9.0 [−13.0; −5.0], (CT+TT) −13.5 [−15.0; −10.0], p = 0.014. The scores on the UKU scale, which was used to evaluate the safety of therapy, were also different: (CC) 7.5 [6.0; 11.0], (CT+TT) 11.0 [8.0; 12.0], p = 0.003.

Conclusion:

Possible relationship between the CYP3A activity, evaluated by the content of the urinary endogenous substrate of the given isoenzyme and its metabolite, the 6-beta-hydroxy cortisol (6-β-HC) / cortisol ratio, and the efficacy of diazepam was demonstrated. This possible relationship was also supported by the genotyping results. This should be taken into consideration when prescribing this drug to such patients in order to reduce the risk of pharmacoresistance.

Keywords

pharmacogenetics benzodiazepines diazepam biotransformation personalized medicine CYP3A alcohol withdrawal syndrome

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References

Fukasawa

Suzuki

Otani

. Effects of genetic polymorphism of cytochrome P450 enzymes on the pharmacokinetics of benzodiazepines. J Clin Pharm Ther. 2007;32(4):333–341.

Sachdeva

Choudhary

Chandra

. Alcohol withdrawal syndrome: benzodiazepines and beyond. J Clin Diagn Res. 2015;9(9):VE01–VE07.

Benedict

Wong

Cassidy

, et al. Predictors of resistant alcohol withdrawal (RAW): a retrospective case-control study. Drug Alcohol Depend. 2018;192:303–308.

Hack

Hoffman

Nelson

. Resistant alcohol withdrawal: does an unexpectedly large sedative requirement identify these patients early? J Med Toxicol. 2006;2(2):55–60.

Sarff

Gold

. Alcohol withdrawal syndromes in the intensive care unit. Crit Care Med. 2010;38(9 suppl):494–501.

Gold

Rimal

Nolan

, et al. A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens. Crit Care Med. 2007;35(3):724–730.

Ashton

. Guidelines for the rational use of benzodiazepines. When and what to use. Drugs. 1994;48(1):25–40.

Bird

Makela

. Alcohol withdrawal: what is the benzodiazepine of choice? Ann Pharmacother. 1994;28(1):67–71.

Weintraub

. Diazepam in the treatment of moderate to severe alcohol withdrawal. CNS Drugs. 2017;31(2):87–95.

10.

Calcaterra

Barrow

. Classics in chemical neuroscience: diazepam (valium). ACS Chem Neurosci. 2014;5(4):253–260.

11.

Dean

. Diazepam therapy and CYP2C19 genotype. In: Pratt

McLeod

Rubinstein

Dean

Kattman

Malheiro

, eds. Medical Genetics Summaries [Internet]. National Center for Biotechnology Information (US); 2012.

12.

Andersson

Miners

Veronese

, et al. Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms. Br J Clin Pharmacol. 1994;38(2):131–137.

13.

Jung

Richardson

Raucy

, et al. Diazepam metabolism by cDNA-expressed human 2C P450 s: identification of P4502C18 and P4502C19 as low K(M) diazepam N-demethylases. Drug Metab Dispos. 1997;25(2):133–139.

14.

Oneda

Crettol

Jaquenoud Sirot

, et al. The P450 oxidoreductase genotype is associated with CYP3A activity in vivo as measured by the midazolam phenotyping test. Pharmacogenet Genomics. 2009;19(11):877–883.

15.

Fukasawa

Yasui-Furukori

Suzuki

, et al. Pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity. Eur J Clin Pharmacol. 2005;61(11):791–795.

16.

Lepper

Baker

Permenter

, et al. Effect of common CYP3A4 and CYP3A5 variants on the pharmacokinetics of the cytochrome P450 3A phenotyping probe midazolam in cancer patients. Clin Cancer Res. 2005;11(20):7398–7404.

17.

Yang

Shou

Korzekwa

, et al. Role of cDNA-expressed human cytochromes P450 in the metabolism of diazepam. Biochem Pharmacol. 1998;55(6):889–896.

18.

Jose

Mathaiyan

Kattimani

, et al. Role of CYP2C19 gene polymorphism in acute alcohol withdrawal treatment with loading dose of diazepam in a South Indian population. Eur J Clin Pharmacol. 2016;72(7):807–812.

19.

Nuss

Elnicki

Dunsworth

, et al. Utilizing CIWA-Ar to assess use of benzodiazepines in patients vulnerable to alcohol withdrawal syndrome. W V Med J. 2004;100(1):21–25.

20.

Lingjaerde

Ahlfors

Bech

, et al. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl. 1987;334:1–100.

21.

Lee

Goldstein

. Functionally defective or altered CYP3A4 and CYP3A5 single nucleotide polymorphisms and their detection with genotyping tests. Pharmacogenomics. 2005;6(4):357–371.

22.

Elens

Bouamar

Hesselink

, et al. The new CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with an increased risk of delayed graft function and worse renal function in cyclosporine-treated kidney transplant patients. Pharmacogenet Genomics. 2012;22(5):373–380.

23.

Denisenko

Sychev

Sizova

, et al. CYP3A and CYP2C19 activity in urine in relation to CYP3A4, CYP3A5, and CYP2C19 polymorphisms in Russian peptic ulcer patients taking omeprazole. Pharmgenomics Pers Med. 2018;11:107–112.

24.

Zastrozhin

Smirnov

Sychev

, et al. CYP3A4 activity and haloperidol effects in alcohol addicts. Int J Risk Saf Med. 2015;27(suppl 1):S23–S24.

25.

Zastrozhin

Grishina

Ryzhikova

, et al. The influence of CYP3A5 polymorphisms on haloperidol treatment in patients with alcohol addiction. Pharmgenomics Pers Med. 2017;11:1–5.

26.

Zastrozhin

Bryun

Skryabin

, et al. Genotyping and phenotyping of CYP2D6 and CYP3A isoenzymes in patients with alcohol use disorder: correlation with haloperidol plasma concentration. Drug Metab Pers Ther. 2017;32(3):129–136.

27.

Lee

Kim

, et al. Distribution of exogenous and endogenous CYP3A markers and related factors in healthy males and females. AAPS J. 2017;19(4):1196–1204.

28.

Lang

Linnet

. The ratio of 6β-hydroxycortisol to cortisol in urine as a measure of cytochrome P450 3A activity in postmortem cases. J Forensic Sci. 2014;59(4):1036–1040.

29.

Lutz

Bittner

Ufer

, et al. Quantification of cortisol and 6 beta-hydroxycortisol in human urine by LC-MS/MS, and gender-specific evaluation of the metabolic ratio as biomarker of CYP3A activity. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878(1):97–101.

30.

Mårde Arrhén

Nylén

Lövgren-Sandblom

, et al. A comparison of 4β-hydroxycholesterol: cholesterol and 6β-hydroxycortisol: cortisol as markers of CYP3A4 induction. Br J Clin Pharmacol. 2013;75(6): 1536–1540.

31.

Galteau

Shamsa

. Urinary 6beta-hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals. Eur J Clin Pharmacol. 2003;59(10):713–733.

32.

Zastrozhin

Savchenko

Bryun

, et al. Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder. Pharmgenomics Pers Med. 2017;(10):209–215.