Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort

Abstract

The relationship between genetic variation in CYP2D6 and variable drug response represents a potentially powerful pharmacogenetic tool. However, little is known regarding this relationship in the genetically diverse South African population. The aim was therefore to evaluate the relationship between predicted and measured CYP2D6 phenotype. An XL-PCR+Sequencing approach was used to determine CYP2D6 genotype in 100 healthy volunteers and phenotype was predicted using activity scores. With dextromethorphan as the probe drug, metabolic ratios served as a surrogate measure of in vivo CYP2D6 activity. Three-hour plasma metabolic ratios of dextrorphan/dextromethorphan were measured simultaneously using semi-automated online solid phase extraction coupled with tandem mass spectrometry. Partial adaptation of the activity score system demonstrated a strong association between genotype and phenotype, as illustrated by a kappa value of 0.792, inter-rater discrepancy of 0.051 and sensitivity of 72.7%. Predicted phenotype frequencies using the modified activity score were 1.3% for poor metabolisers (PM), 7.6% for intermediate metabolisers (IM) and 87.3% for extensive metabolisers (EM). Measured phenotype frequencies were 1.3% for PM, 13.9% for IM and 84.8% for EM. Comprehensive CYP2D6 genotyping reliably predicts CYP2D6 activity in this South African cohort and can be utilised as a valuable pharmacogenetic tool.

Evaluation of CYP2D6 phenotype in the Yoruba Nigerian population

“…The age range in this study was similar to previous studies investigating CYP2D6 phenotype [24, 30, 31]. The established tolerability profile of dextromethorphan was further demonstrated by the fact that only one (~1%) participant in our study had mild and transient drowsiness [24, 28, 31–33]. In CYP2D6 phenotyping, the requisite cutoff(s) may be obtained by subjecting data to a probit analysis, Receiver Operating Characteristics (ROC) or other similar statistical analysis [28, 33, 34].…”

“…It is also noteworthy that the two poor metabolizers that were identified were aged 25 and 27 years. The age range in this study was similar to previous studies investigating CYP2D6 phenotype [24, 30, 31]. The established tolerability profile of dextromethorphan was further demonstrated by the fact that only one (~1%) participant in our study had mild and transient drowsiness [24, 28, 31–33].…”

“…Ebeshi et al obtained a prevalence of 3.5% poor metabolizers with urinary dextromethorphan/dextrorphan metabolic ratio among heterogeneous Nigerians[24]. Other studies in Africa also showed a poor metabolizer prevalence of 1.2% in South Africa [31] and 1–4% in other African countries [20, 21, 49]. These findings are similar to that of Asian countries with a poor metabolizer prevalence of 1–4% [16, 17, 33].…”

“…Gaedigk et al[58], and Zineh et al[59], have proposed an Activity Score (AS) that are calculated from the CYP2D6 gene and use to determine the CYP2D6 metabolic activities of an individual. Vanwong et al using risperidone as a probe [60], Puangpetch et al [61], in Thailand, and Dodgen et al in South Africa [31], reported a good correlation between AS, CYP2D6 genotypes and measured phenotypes.…”

Understanding human genetic factors influencing primaquine safety and efficacy to guide primaquine roll-out in a pre-elimination setting in southern Africa

“…In sub-Saharan Africa, prevalence of G6PD deficiency is estimated to range between 5 and 37.5% [ 9 ], and CYP2D6 allele frequencies range from 1 to 33% [ 28 ]. South Africa has previously (1940s–1980s) reported fewer cases of G6PD deficiency (5.3%) [ 29 , 30 ] and CYP2D6 (2.6 % ) [ 31 ] mutations compared to its neighbouring countries, most likely a consequence of genetic differences among the distinct ethnic groups [ 32 , 33 ]. However, recent population movements and immigration [ 34 ] may have led to shifts in the frequency of the enzyme deficiency and CYP2D6 variants across the country.…”