ABSTRACT
AIM: This study aimed to assess the impact of CYP2D6 and CYP2C19 variation on venlafaxine (VEN) at steady state in patients from Trinidad and Tobago of Indian and African descent with major depressive disorder. PATIENTS & METHODS: Patients were phenotyped with dextromethorphan, genotyped for CYP2D6 and CYP2C19, and metabolic ratios for VEN obtained at 2-week intervals. RESULTS: Of 61 patients, 55 were genotyped and phenotyped and 47 completed 8 weeks of VEN treatment. The majority of patients had metabolic ratios for VEN that were consistent with those for dextromethorphan and genotype-predicted phenotype using activity scores. One subject presented with a novel no-function allele, CYP2D6*99. No correlations were observed with CYP2C19 genotype. CONCLUSION: CYP2D6 genotype analysis provides valuable information to individualize drug therapy with VEN.
Subject(s)
Cytochrome P-450 CYP2D6/genetics , Depressive Disorder, Major/drug therapy , Polymorphism, Single Nucleotide , Serotonin and Noradrenaline Reuptake Inhibitors/metabolism , Venlafaxine Hydrochloride/metabolism , Adult , Black People/genetics , Depressive Disorder, Major/blood , Depressive Disorder, Major/enzymology , Female , Gene Frequency , Genotype , Humans , Indians, South American/genetics , Male , Serotonin and Noradrenaline Reuptake Inhibitors/blood , Serotonin and Noradrenaline Reuptake Inhibitors/therapeutic use , Trinidad and Tobago , Venlafaxine Hydrochloride/blood , Venlafaxine Hydrochloride/therapeutic useABSTRACT
BACKGROUND: The highly polymorphic CYP2D6 gene has extensively been studied in many populations, but there is a void of knowledge regarding CYP2D6 pharmacogenetics and activity in populations with unique ancestries and admixture, such as those residing in Trinidad and Tobago. MATERIALS & METHODS: 167 healthy Indo- and 103 Afro-Trinidadians were phenotyped with dextromethorphan and extensively genotyped. Gene resequencing was performed to resolve cases with genotype/phenotype discordance. RESULTS: CYP2D6 activity did not differ between the Indo-Trinidadians and Afro-Trinidadians. Poor metabolizers were, however, more frequent in the Indo-Trinidadians (4.19 vs 1.94%), and unique allele frequency patterns were observed. Two novel nonfunctional allelic variants were found among the Indo-Trinidadians in two discordant cases. CYP2D6*100 is characterized by a single nucleotide deletion and CYP2D6*101 by a 19-bp deletion; both cause frameshifts. CONCLUSION: Our study underscores the importance of thoroughly characterizing the genetic make up of unique populations when considering pharmacogenetic testing for individualized therapy.
