Treatment of Iraqi People with Hyperkinetic Movement Disorders by Tetrabenazine in Relation to Genetic Polymorphism of CYP450 2D6

Abstract

Genetic polymorphism is defined as the inheritance of a trait controlled by a single genetic locus with two alleles in which the least common allele has a frequency of about 1% or greater. The Cytochrome P450 (CYP2D6) enzyme metabolizes about 25% of clinically used drugs from many different drug classes including antidepressants, antipsychotics, antihypertensives, and analgesics. The CYP2D6 is a highly polymorphic gene locus with more than 75 allelic variants, thus subjects can be classified into poor metabolizers (PM), ), intermediate metabolizers (IMs), extensive metabolizers (EM), or ultra-rapid metabolizers (UM) of a given CYP2D6 substrate. By using pharmacogenomics, the pharmacotherapy can be optimized, thereby increasing the treatments overall efficacy and decreasing the incidence of adverse events. The present study is aimed to predicted phenotypes of CYP2D6 as : poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultra rapid metabolizers for tetrabenazine in patients with hyperkinetic movement disorders compared to healthy subjects in Iraq . The study was carried on 75 subjects participated (30 male, 45 female) ; fifty of them were with hyperkinetic movement disorders( 25 dystonia , 25 chorea ) the reminder 25 were healthy . Genotyping of CYP2D6 gene was performed by polymerase chain reaction (PCR) conventional (allele specific method). Plasma concentration of Tetraberazine was measured by High-performance liquid chromatography (HPLC) . Data were collected through direct interview with the subjects besides the assessment of genetic polymorphism of CYP 450 2D6 enzyme for Iraqi people. The results of this study show there were a significant CYP 450 2D6 enzyme polymorphism. the number (percentage) of subjects with CYP 450 2D6 gene polymorphisms was 17 (22.66%) of the total study population. The number (percentage) of subjects with CYP 450 2D6*2 was 58 (76.32%), whereas, subjects with CYP450 2D6 *10 was 17 (22.66%).However , no subjects were observed with CYP 450 2D6 *4 polymorphisms in this study. The tetrabenazine concentration with mean ± SD was 3.08± 0.231 and 2.506±0.235 ng/ml for chorea and dystonia patients respectively , while alpha and beta dihydrotetrabenazine range was 37.72± (2.18 ng/ml _38.13± 2.00 ng/ml ) and (21.376±0.583ng/ml_ 18.252±0.874ng/ml ) respectively .