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

Abstract

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.

The relationship between the CYP2C19*17 genetic polymorphism and the efficacy and safety of diazepam in patients with alcohol withdrawal syndrome

“… òî aeå âðåìÿ ìîaeíî ïðåäïîëîaeèòü, ÷òî ó íîñèòåëåé íåìóòàíòíîãî ãåíîòèïà ïî ïîëèìîðôíîìó ìàðêåðó -806C>T (rs12248560) ãåíà CYP2C19 èìååòñÿ áîëåå âûñîêèé ðèñê ðàçâèòèÿ ÍËÐ íà ôîíå òåðàïèè äèàçåïàìîì. Óñïåøíûå ðåçóëüòàòû ðàíåå ïðîâåäåííûõ íàøåé èññëåäîâàòåëüñêîé ãðóïïîé ðàáîò ïî èç-ó÷åíèþ ôàðìàêîãåíîìíûõ áèîìàðêåðîâ íà ïðèìåðå ïîëèìîðôèçìà ãåíîâ CYP2D6 [27,28,30], CYP3A5 [20,21,25] è ABCB1, êîäèðóþùåãî ãëèêîïðîòåèí P, [26,28,29], à òàêaeå ôàðìàêîìåòàáîëîìíûõ áèîìàðêåðîâ [22][23][24] äëÿ îïòèìèçàöèè ðåaeèìà äîçèðîâàíèÿ ãàëîïåðèäîëà ó ïàöèåíòîâ ñ àëêîãîëüíîé çàâèñèìîñòüþ ïîäòâåðaeäàþò âàaeíîñòü ïåðñîíàëèçèðîâàííîãî ïîäõîäà ê íàçíà÷åíèþ áåíçîäèàçåïèíîâ (è êîíêðåòíî äèàçåïàìà) ó äàííîé êàòåãîðèè ïàöèåíòîâ.…”

Background sensitivity to chemotherapy-induced nausea and vomiting and response to antiemetics in paediatric patients: a genetic association study

“…Another potential candidate gene for pharmacogenetic studies of CINV is SLC6A3, encoding the dopamine transporter. Polymorphisms in SLCA63 have been associated with response to dopamine D2 receptor antagonists for schizophrenia or alcohol dependence [18,19].…”

Effect of ADRA2A gene polymorphisms on the anesthetic and analgesic effects of dexmedetomidine in Chinese Han women with cesarean section

“…In drug therapy, susceptibility to toxic or inadequately treated individuals is important. Genetic polymorphisms of genes responsible for drug reactions are expected to be used to track differences between individuals (29). The influence of genetic factors is not clear.…”