Phenoconversion of Cytochrome P450 Metabolism: A Systematic Review

Abstract

Phenoconversion is the mismatch between the individual's genotype-based prediction of drug metabolism and the true capacity to metabolize drugs due to nongenetic factors. While the concept of phenoconversion has been described in narrative reviews, no systematic review is available. A systematic review was conducted to investigate factors contributing to phenoconversion and the impact on cytochrome P450 metabolism. Twenty-seven studies met the inclusion criteria and were incorporated in this review, of which 14 demonstrate phenoconversion for a specific genotype group. Phenoconversion into a lower metabolizer phenotype was reported for concomitant use of CYP450-inhibiting drugs, increasing age, cancer, and inflammation. Phenoconversion into a higher metabolizer phenotype was reported for concomitant use of CYP450 inducers and smoking. Moreover, alcohol, pregnancy, and vitamin D exposure are factors where study data suggested phenoconversion. The studies reported genotype-phenotype discrepancies, but the impact of phenoconversion on the effectiveness and toxicity in the clinical setting remains unclear. In conclusion, phenoconversion is caused by both extrinsic factors and patient- and disease-related factors. The mechanism(s) behind and the extent to which CYP450 metabolism is affected remain unexplored. If studied more comprehensively, accounting for phenoconversion may help to improve our ability to predict the individual CYP450 metabolism and personalize drug treatment.

Keywords: CYP2C19; CYP2D6; CYP3A5; comorbidities; concomitant medication; cytochrome P450; personalized medicine; pharmacogenetics; phenoconversion.

Figure 1

Study flow diagram of the retrieval and review process (Appendix A).

Figure 2

Cytochrome P450-mediated drug metabolism can be inhibited or induced by the presence of co-medication and/or comorbidities, for which the magnitude of the changes depends on the host’s genotype. The metabolite concentrations in blood are plotted for the genotype-based predicted phenotypes (UM, NM, IM, and PM). This is presented for the normal situation (A) and for scenarios in which (B) CYP450 activity is inhibited by concomitant medication or (C) induced by a comorbidity. The resulting effects on drug efficacy are opposing for drugs and prodrugs. UM = ultra-rapid metabolizer, NM = normal metabolizer, IM = intermediate metabolizer, PM = poor metabolizer.