Findings may improve personalised drug prescription and adverse drug reactions.
A new in vivo pharmacokinetic recall study involving 114 participants in the Estonian Biobank has provided the first clinical confirmation that previously uncharacterized genetic variants in the drug-metabolising enzymes CYP2C19 and CYP2D6 significantly affect how drugs are processed in the human body. These results emphasise the need to look beyond common pharmacogenetic markers to improve the precision of personalised drug therapy.
Cytochrome P450 enzymes such as CYP2C19 and CYP2D6 are responsible for the metabolism of 35-40% of drugs in clinical use. These include medications for cardiovascular disease, psychiatric conditions, gastric acid disorders, and other common indications. Despite well-established standard allele panels used in clinical pharmacogenetics, many rare or structural variants remain uncharacterized, making it difficult to accurately predict metabolic phenotype for all individuals.
In the study, researchers from the University of Tartu, Tartu University Hospital, North Estonia Medical Centre administered single oral doses of the probe drugs omeprazole (a CYP2C19 substrate) and metoprolol (a CYP2D6 substrate) to volunteers with rare or novel variants identified through sequencing of their genomes. According to prof. Lili Milani, Head of Estonian Biobank, plasma drug and metabolite concentrations were measured at ten time points to calculate drug and metabolite ratios, providing direct in vivo estimates of enzymatic activity.
In collaboration with experts from Oslo University and Karolinska Institutet, the researchers found that deletions in CYP2C19 – specifically alleles referred to as CYP2C19*37 and CYP2C19*42 (a novel deletion spanning over exon 2-5) – were strongly associated with a poor metabolizer phenotype, confirming that these variants lead to substantially reduced metabolic activity.
The study also presented clinical evidence of reduced CYP2D6 enzyme activity associated with the CYP2D6*124 allele and a novel missense variant (c.940C>A) in exon 6. Exposure to concomitant enzyme inhibitors was significantly associated with higher metabolic ratios for both CYP2C19 and CYP2D6, demonstrating that drug–drug interactions can further modify metabolic phenotype beyond genetic predictions.
Implications for Personalised Medicine
These findings highlight limitations of traditional pharmacogenetic testing that focuses on a small set of "standard" star alleles, such as those commonly used in CPIC guidelines. Rare and structural variants – particularly those enriched in specific populations – may have significant clinical impact but are often missed in routine genotyping. "The new data suggest that incorporating broader variant discovery by long-read HiFi sequencing and phenotyping strategies accounting for drug-drug interactions can improve metabolic phenotype assignment and support more precise drug dosing recommendations," said Milani.
Senior authors of the study note that combining in vivo pharmacokinetic phenotyping with advanced sequencing technologies enables a more accurate understanding of how genetic variation influences drug metabolism in real patients, which is critical for safer and more effective use of many widely prescribed medications.
