Relevance of Pharmacogenomics, CYP450 genes and their genetic variations in drug metabolism and toxicity

Background: Variations in drug responses are related to inherited characteristics of the genome that cause a wide variability in individual responses to drugs. Pharmacogenetics or pharmacogenomics analyses help us to understand DNA variations that are related to drug action (pharmacodynamics) and drug disposition (pharmacokinetics). Using a pharmacogenomics (PGx) approach, we studied different CYP450 genes that are associated with drug metabolism, along with their genomic variants, thus strengthening our understanding of personalized medicines.

Methods: We downloaded the PGx database from the FDA website and collated the data utilizing various evolutionary tools and software. We also provided an overview of current progress in computational approaches for the prediction of drug metabolism and toxicity using a combination of knowledge graph- and AI-based approaches. Utilizing ethnicity data from published sources, we also correlated the clinical implications of drug metabolism and toxicity variability in different population cohorts.

Results: We observed that 42 unique drugs catering to nine different therapeutic areas are associated with six CYP450 (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A5) genes/biomarkers and 32 unique variants/SNPs. The allelic frequencies (AFs) of the 32 variants were also studied in different population ethnicity groups (from a published database). We observed unique combinations of drugs, biomarkers and variant associations that highlight how the metabolism of a drug is controlled/regulated/metabolized by the genetic basis of an individual. We observed 32 unique combinations where the same CYP biomarker and its variant are shared by different drugs associated with different therapeutic areas.

Conclusions: PGx studies should be inclusive, and policy makers/drug regulators should include such approaches for better understanding the genetic basis of drug-metabolizing genes for better drug response. The PGx approach also highlights a significant association between Precision Medicine and Pharmacovigilance by understanding drug metabolism and toxicity in accordance with an individual’s genetic makeup.