To Genotype or Phenotype for Personalized Medicine? CYP450 Drug Metabolizing Enzyme Genotype–Phenotype Concordance and Discordance in the Ecuadorian Population

Abstract

Genetic variations within the cytochrome P450 (CYP450) superfamily of drug metabolizing enzymes confer substantial person-to-person and between-population differences in pharmacokinetics, and by extension, highly variable clinical effects of medicines. In this context, "personalized medicine," "precision medicine," and "stratified medicine" are related concepts attributed to what is essentially targeted therapeutics and companion diagnostics, aimed at improving safety and effectiveness of health interventions. We report here, to the best of our knowledge, the first comparative clinical pharmacogenomics study, in an Ecuadorian population sample, of five key CYP450s involved in drug metabolism: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. In 139 unrelated, medication-free, and healthy Ecuadorian subjects, we measured the phenotypic activity of these drug metabolism pathways using the CEIBA multiplexed phenotyping cocktail. The subjects were genotyped for each CYP450 enzyme gene as well. Notably, based on the CYP450 metabolic phenotypes estimated by the genotype data, 0.75% and 3.10% of the subjects were genotypic poor metabolizers (gPMs) for CYP2C19 and CYP2D6, respectively. Additionally, on the other extreme, genotype-estimated ultrarapid metabolizer (gUMs) phenotype was represented by 15.79% of CYP2C19, and 5.43% of CYP2D6. There was, however, considerable discordance between directly measured phenotypes (mPMs and mUMs) and the above genotype-estimated enzyme phenotypes. For example, among individuals genotypically carrying enhanced activity alleles (gUMs), many showed a lower actual drug metabolism capacity than expected by their genotypes, even lower than individuals with reduced or no activity alleles. In conclusion, for personalized medicine in the Ecuadorian population, we recommend CYP450 multiplexed phenotyping, or genotyping and phenotyping in tandem, rather than CYP450 genotypic tests alone. Additionally, we recommend, in consideration of equity, ethical, and inclusive representation in global science, further precision medicine research and funding in support of neglected or understudied populations worldwide.

No Effect of Dose Adjustment to the CYP2D6 Genotype in Patients With Severe Mental Illness

“…The present study supports this hypothesis by showing no differences in plasma levels of drugs in the different phenotypes. Another clinical study showed, that a proportion of healthy individuals with a PM genotype are phenotypically EMs as measured by CEIBA metabolization ( 43 ).…”

Evaluation of CYP2D6 phenotype in the Yoruba Nigerian population

“…However, CYP2D6 genotype-phenotype matching alone may not produce a desirable result, as studies have reported discordance in genotype-predicted PMs [54–56], and recent studies also suggested that CYP2D6 genotype was not a good predictor of ultra rapid metabolism[18, 19, 57]. 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.…”

“…The prevalence of CYP2D6 phenotypes varies among different populations and races: studies showed 7– 10% PMs among Caucasians [14, 15], 1–2% PMs in the Asian populations [16, 17], 6.9% PMs in the Cuban populations [18], 3.1% PMs in the Ecuadorian populations[19], and 1–4% PMs population in Africa [20–23]. In Nigeria, few available studies among the many ethnic populations indicate a prevalence of PMs of 0–3.5% [24, 25].…”

Can the CEIBA Cocktail Designed for Human Cytochrome P450 Enzymes be Used in the Rat for Drug Interaction Studies?

“…The global aim of this work was to assess the usefulness of the CEIBA cocktail in the nonclinical evaluation of metabolic-based drug interactions in Wistar rats, as it was originally designed and utilised to measure the specific-metabolic activity of CYP isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) in humans (41). Several important differences between human and rat CYP isoenzymes involved in the metabolism of the four probe drugs of the CEIBA cocktail were previously confirmed, as shown in Table 3 (26,(42)(43)(44)(45)(46).…”