Genotyping and phenotyping of CYP2D6 and CYP3A isoenzymes in patients with alcohol use disorder: correlation with haloperidol plasma concentration
-
Dmitry A. Sychev
,
Igor I. Miroshnichenko
Abstract
Background:
Haloperidol is used for the treatment of alcohol use disorders in patients with signs of alcohol-related psychosis. Haloperidol therapy poses a high risk of adverse drug reactions (ADR). Contradictory data, which include the effects of genetic polymorphisms in genes encoding the elements of haloperidol biotransformation system on haloperidol metabolism rate and plasma drug concentration ratio, are described in patients with different genotypes. The primary objective of this study was to investigate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on haloperidol equilibrium concentration in patients with alcohol use disorder.
Methods:
The study included 69 male patients with alcohol use disorder. Genotyping was performed using the allele-specific real-time PCR. CYP2D6 and CYP3A were phenotyped with HPLC-MS using the concentration of endogenous substrate of the enzyme and its urinary metabolites [6-hydroxy-1,2,3,4-tetrahydro-β-carboline(6-HO-THBC) to pinoline ratio for CYP2D6 and 6-β-hydroxycortisol to cortisol ratio for CYP3A]. The equilibrium plasma concentration was determined using LC-MS-MS.
Results:
Results indicated that both C/D indexes and equilibrium concentration levels depend on CYP2D6 genetic polymorphism, but only in patients receiving haloperidol intramuscular injections [0.26 (0.09; 0.48) vs. 0.54 (0.44; 0.74), p=0.037].
Conclusions:
The study demonstrates that CYP2D6 genetic polymorphism (1846G>A) can affect haloperidol concentration levels in patients with alcohol use disorder.
Acknowledgments
The authors are grateful to the head physician of the Moscow Research and Practical Centre on Addictions Elena Sokolchik for research assistance. The authors would also like to thank Dr. Albert Aguzarov, Dr. Sergey Pahomov, Dr. Oleg Matis, Dr. Natalia Sannikova, Dr. Aleksey Ivanuyk, Dr. Yuiliya Petrosyan, Dr. Tatjana Galaktionova, and Dr. Andrey Vdovin for their excellent clinical assistance.
Author contributions: DAS, MSZ1, IIM, LMS, and EAB analyzed the data. DAS, MSZ1, LMS, and EAB conceived and designed the study and supervised the work. DAS, MSZ1, IIM, NVB, EAG, LMS, and EAB wrote the reply to the reviewers and the revised manuscript. MSZ2 recruited the patients. EAG, KAR, KBM, DDM, NES, and ASS performed the genotyping of CYP2D6 and CYP3A5. VVS performed the phenotyping of CYP2D6 and CYP3A. IIM and NVB performed TDM. VS and PN performed translation. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved its submission.
Research funding: This work was supported by the Russian Science Foundation under the project 16-15-00227 “Fundamental research and exploratory research in priority areas of research.”
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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©2017 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Original Articles
- Genotyping and phenotyping of CYP2D6 and CYP3A isoenzymes in patients with alcohol use disorder: correlation with haloperidol plasma concentration
- Evaluation of the Ecstasy influence on tramadol and its main metabolite plasma concentration in rats
- Imatinib quantification in human serum with LC-MS3 as an effective way of protein kinase inhibitor analysis in biological matrices
- Preliminary study of the association between the elimination parameters of phenytoin and phenobarbital
- Effects of the genetic variants of organic cation transporters 1 and 3 on the pharmacokinetics of metformin in Jordanians
- Short Communications
- Carboxylesterase 1A2 encoding gene with increased transcription and potential rapid drug metabolism in Asian populations
- Need for pharmacogenetic studies on the prevalence of MTHFR mutations in Puerto Ricans and Hispanics
Artikel in diesem Heft
- Frontmatter
- Original Articles
- Genotyping and phenotyping of CYP2D6 and CYP3A isoenzymes in patients with alcohol use disorder: correlation with haloperidol plasma concentration
- Evaluation of the Ecstasy influence on tramadol and its main metabolite plasma concentration in rats
- Imatinib quantification in human serum with LC-MS3 as an effective way of protein kinase inhibitor analysis in biological matrices
- Preliminary study of the association between the elimination parameters of phenytoin and phenobarbital
- Effects of the genetic variants of organic cation transporters 1 and 3 on the pharmacokinetics of metformin in Jordanians
- Short Communications
- Carboxylesterase 1A2 encoding gene with increased transcription and potential rapid drug metabolism in Asian populations
- Need for pharmacogenetic studies on the prevalence of MTHFR mutations in Puerto Ricans and Hispanics
