The correlation between CYP2D6 isoenzyme activity and haloperidol efficacy and safety profile in patients with alcohol addiction during the exacerbation of the addiction

Sychev, D. A.; Застрожин, Михаил Сергеевич; Смирнов, В. В.; Grishina, Elena A.; Savchenko, L. M.; Bryun, Evgeny А.

doi:10.2147/pgpm.s110385

Cited by 15 publications

(7 citation statements)

References 8 publications

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“…It is important to note that pharmacokinetics can also affect the personal response to haloperidol. In our previous works, we showed the effect of CYP2D6 polymorphism (and its activity) 21 and the activity of CYP3A4 28 on haloperidol efficacy and safety.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder

Застрожин¹,

Brodyansky²,

Skryabin³

et al. 2017

PGPM

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BackgroundAntipsychotic action of haloperidol is due to blockade of D2 receptors in the mesolimbic dopamine pathway, while the adverse drug reactions are associated with striatal D2 receptor blockade. Contradictory data concerning the effects of genetic polymorphisms of genes encoding these receptors and associated structures (catechol-O-methyltransferase [COMT], glycine transporter and gene encoding the density of D2 receptors on the neuronal membrane) are described.ObjectiveThe objectives of this study were to evaluate the correlation between DRD2, SLC6A3 (DAT) and COMT genetic polymorphisms and to investigate their effect on the development of adverse drug reactions in patients with alcohol-use disorder who received haloperidol.Patients and methodsThe study included 64 male patients (average age 41.38 ± 10.14 years, median age 40 years, lower quintile [LQ] 35 years, upper quintile [UQ] 49 years). Bio-Rad CFX Manager™ software and “SNP-Screen” sets of “Syntol” (Russia) were used to determine polymorphisms rs4680, rs1800497, rs1124493, rs2242592, rs2298826 and rs2863170. In every “SNP-Screen” set, two allele-specific hybridizations were used, which allowed to determine two alleles of studied polymorphism separately on two fluorescence channels.ResultsResults of this study detected a statistically significant difference in the adverse drug reaction intensity in patients receiving haloperidol with genotypes 9/10 and 10/10 of polymorphic marker SLC6A3 rs28363170. In patients receiving haloperidol in tablets, the increases in the UKU Side-Effect Rating Scale (UKU) score of 9.96 ± 2.24 (10/10) versus 13 ± 2.37 (9/10; p < 0.001) and in the Simpson-Angus Scale (SAS) score of 5.04 ± 1.59 (10/10) versus 6.41 ± 1.33 (9/10; p = 0.006) were revealed.ConclusionPolymorphism of the SCL6A3 gene can affect the safety of haloperidol, and this should be taken into account during the choice of drug and its dosage regimen.

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Section: Discussionmentioning

confidence: 99%

“…In our previous works, we showed the effect of CYP2D6 polymorphism (and its activity)21 and the activity of CYP3A428 on haloperidol efficacy and safety.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder

Застрожин¹,

Brodyansky²,

Skryabin³

et al. 2017

PGPM

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“… 4 The investigations we performed earlier, which involved alcohol-addicted patients, have shown the existence of statistically significant correlation between CYP2D6 gene polymorphisms, activity of this isoenzyme, and the efficacy and safety of haloperidol. 5 …”

Section: Introductionmentioning

confidence: 99%

The influence of CYP3A5 polymorphisms on haloperidol treatment in patients with alcohol addiction

Застрожин

Grishina

Ryzhikova

et al. 2017

PGPM

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BackgroundIsoenzymes CYP2D6 and CYP3A4, the activity of which varies widely, are involved in metabolism of haloperidol and may influence its profile of efficacy and safety.ObjectiveThe primary aim of this study was to estimate the relationship between CYP3A5 gene polymorphism, activity of the CYP3A isoenzyme, and the risk of development of adverse drug reactions by haloperidol in patients with alcohol abuse.MethodsSixty-six male alcohol-addicted patients participated in the study. The safety of haloperidol was evaluated by Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) and Simpson–Angus Scale for extrapyramidal symptoms (SAS). The activity of CYP3A was evaluated by determining the concentrations of an endogenous substrate of this isoenzyme (cortisol) and its urinary metabolite (6-beta-hydroxycortisol, 6-B-HC). Genotyping of CYP3A5*3 was performed by real-time polymerase chain reaction with allele-specific hybridization.ResultsThe frequency of A-allele occurrence in Russian population was very poor (2.27%). CYP3A5*3 polymorphism had no influence on safety profile indicators of haloperidol (UKU scale: p=0.55, SAS scale: p=0.64). In addition, there was no statistical significant difference between the values of indexes of the metabolic ratio (6-B-HC/cortisol) in groups with different genotypes of CYP3A5*3: GG 5.00 (3.36; 6.39) vs AG 5.26 (2.10; 6.78) (p=0.902).ConclusionThe frequency of A-allele occurrence of CYP3A5*3 in Russian population is very poor, and it has no high influence on the safety of haloperidol treatment; therefore, there are no reasons to take this polymorphism into account in patients with alcohol addiction who receive haloperidol.

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“…It has high protein binding (90%), large volume of distribution (Vd) (1000–3000 L), and is predominantly metabolized by the liver and gut via glucuronidation (40–50%), CYP3A4 (25–30%), and CYP2D6 (25–30%) [ 15 , 16 , 17 , 18 ]. Previous studies have shown that CYP2D6 genetic polymorphism influences the haloperidol concentration levels in non-ICU patients [ 19 , 20 ]. For CYP3A4, the isoenzyme activity caused concentration changes only at higher doses [ 21 ] The glucuronidation is a major metabolism pathway of haloperidol [ 22 ], but only in vitro studies have shown that this pathway might cause inter-individual concentration variance [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Haloperidol in Critically Ill Patients: Is There an Association with Inflammation?

Sassen

Jagt

et al. 2022

Pharmaceutics

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Haloperidol is considered the first-line treatment for delirium in critically ill patients. However, clinical evidence of efficacy is lacking and no pharmacokinetic studies have been performed in intensive care unit (ICU) patients. The aim of this study was to establish a pharmacokinetic model to describe the PK in this population to improve insight into dosing. One hundred and thirty-nine samples from 22 patients were collected in a single-center study in adults with ICU delirium who were treated with low-dose intravenous haloperidol (3–6 mg per day). We conducted a population pharmacokinetic analysis using Nonlinear Mixed Effects Modelling (NONMEM). A one-compartment model best described the data. The mean population estimates were 51.7 L/h (IIV 42.1%) for clearance and 1490 L for the volume of distribution. The calculated half-life was around 22 h (12.3–29.73 h) for an average patient. A negative correlation between C-Reactive Protein (CRP) and haloperidol clearance was observed, where clearance decreased significantly with increasing CRP up to a CRP concentration of 100 mg/L. This is the first step towards haloperidol precision dosing in ICU patients and our results indicate a possible role of inflammation.

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The correlation between CYP2D6 isoenzyme activity and haloperidol efficacy and safety profile in patients with alcohol addiction during the exacerbation of the addiction

Cited by 15 publications

References 8 publications

Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder

Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder

The influence of CYP3A5 polymorphisms on haloperidol treatment in patients with alcohol addiction

Pharmacokinetics of Haloperidol in Critically Ill Patients: Is There an Association with Inflammation?

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