IMPLICATIONS OF CYP2D6 POLYMORPHISMS FOR THERAPEUTIC DRUG MONITORING IN PATIENTS WITH HYPERTENSION

Abstract

Objective: When using therapeutic drug monitoring for evaluating non-adherence, serum concentrations of drugs are related to the actual intake, but also to pharmacokinetic variability. We aimed to map CYP2D6 polymorphisms in treated hypertensive patients and assess implications for a previous classification of adherence. Metoprolol is predominantly metabolized by CYP2D6, and is the most commonly prescribed beta-blocker in our population. Reduced metabolism can lead to increased concentrations of this drug, potentially causing more side effects and erroneous evaluation of adherence. Design and method: In a multicenter study we mapped CYP2D6 polymorphisms retrospectively in 331 patients being prescribed at least 2 antihypertensive agents, already reported as adherent or non-adherent based on serum concentrations of antihypertensive drugs by mass-spectrometry (UPLC-MS/MS). The CYP2D6 panel included the non-functional variants (null) 2D6*3, 2D6*4, 2D6*5, 2D6*6, 2D6*13 and 2D6*68, and the reduced-functional variants (red) 2D6*9, 2D6*10 and 2D6*41. 2D6*2 or absence of the assayed variant alleles was interpreted as 2D6*1 (wild-type). Patients with *null/*null and absent enzyme activity were classified as poor metabolizers, and patients with *null/*wild-type or *null/*red and varied degree of reduced enzyme activity as intermediate metabolizers. Normal metabolizers included homozygote wildtype and *wildtype/*red. Patients with duplications of functional alleles, leading to increased enzyme activity, were classified as ultra-rapid metabolizers. Results: Based on genotype, 117 patients (35.3%) were intermediate-, 21 (6.3%) were poor- and 3 (0.9%) were ultra-rapid metabolizers, comparable to the European reference population. The low frequency of ultra-rapid metabolizers did not affect the classification of non-adherence. Serum concentrations of metoprolol were related to the CYP2D6 genotype. Some (perhaps 5–10%) non-adherent patients with absent or severely reduced enzyme activity may have been misclassified as adherent; with a higher serum concentration of metoprolol due to poor metabolism rather than excellent adherence. Conclusions: In 331 hypertensive patients with a normal distribution of CYP2D6 polymorphisms, the genotype seemed to influence the serum concentration of metoprolol, but did not affect the classification of non-adherence. However, perhaps 5–10% of the non-adherent patients with reduced metabolism may have been misclassified as adherent.