Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort.
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.
Department of Pharmacology, University of Pretoria, Pretoria, South Africa.|Department of Immunology and Institute for Cellular and Molecular Medicine, University of Pretoria, Pretoria, South Africa.
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Dodgen
Inqaba Biotechnical Industries, Pretoria, South Africa.
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Labuschagne
Department of Immunology and Institute for Cellular and Molecular Medicine, University of Pretoria, Pretoria, South Africa.
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van Schalkwyk
Inqaba Biotechnical Industries, Pretoria, South Africa.
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Steffens
Department of Statistics, University of Pretoria, Pretoria, South Africa.
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Gaedigk
Department of Pharmacology, University of Pretoria, Pretoria, South Africa.
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Cromarty
Division of Clinical Pharmacology, Toxicology & Innovative Therapeutics, Children's Mercy, and School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.
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Alessandrini
Division of Clinical Pharmacology, Toxicology & Innovative Therapeutics, Children's Mercy, and School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.|Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
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Pepper
D000328:Adult; D044466:Asian People / Q000235:genetics; D001711:Biotransformation / Q000235:genetics; D044383:Black People / Q000235:genetics; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D003915:Dextromethorphan / Q000097:blood / Q000378:metabolism*; D003917:Dextrorphan / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D000071185:Pharmacogenomic Testing / Q000379:methods; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D013019:South Africa; D053719:Tandem Mass Spectrometry; D044465:White People / Q000235:genetics; D055815:Young Adult
D003917:Dextrorphan; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6