Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment

Abstract

The beta1 selective beta-blocker metoprolol is metabolized predominantly but not exclusively by CYP2D6. Due to the polymorphism of the CYP2D6 gene, CYP2D6 activity varies markedly between individuals. Consequently, after short-term administration metoprolol plasma concentrations were found to be several fold higher in poor metabolizers than in extensive metabolizers. However, it is currently not known, whether the impact of the CYP2D6 polymorphism persists during long-term therapy, since alternate mechanisms of elimination or metabolism could be effective in this setting. The study comprised 91 Caucasian patients on long-term treatment with metoprolol (median duration of treatment 12.6 months; median daily drug dose: 47.5 mg/day). Metoprolol and alpha-OH-metoprolol plasma concentrations were assessed by HPLC. Genotyping detected the null alleles (*0): *3, *4, *5, *6, *7, *8, *12, *14, *15, the alleles *9, *10 and *41 associated with reduced enzymatic activity as well as the fully functional alleles *1 and *2. Genotype and allele frequencies were in accordance with published frequencies for the German population. The plasma metabolic ratio of metoprolol/alpha-OH-metoprolol was markedly affected by the genotype (P < 0.0001). In accordance, median adjusted metoprolol plasma concentrations were 6.2- and 3.9-fold higher in patients with *0/*0 genotypes (n = 8) and intermediate genotypes (n = 10), respectively, as compared to those with two fully functional alleles (n = 31; P < 0.01). In summary, the pronounced effect of the CYP2D6 genotype persists during long-term therapy, affecting both metabolic ratio and metoprolol plasma concentration.

A Physiologic Approach to the Pharmacogenomics of Hypertension

“…Poor metabolizers also have corresponding changes in their ratio of metoprolol to alpha-hydroxy-metoprolol metabolite 4 .…”

CYP2D6 genotype and its relationship with metoprolol dose, concentrations and effect in patients with systolic heart failure

“…Early studies showed that patients who have no functional alleles of CYP2D6 (poor metabolisers (PMs)), who comprise approximately 7% of the Caucasian population, 5 achieve 3-to 6-fold higher concentrations of racemic metoprolol than extensive metabolisers (EMs) after a single-dose 6,7 and with repeated dosing. [8][9][10][11] Stereoselective metabolism exists, with the inactive R-enantiomer more dependent on CYP2D6 for metabolism, as indicated by an S/R concentration ratio of B1.1 and 1.7 in PMs versus EMs, respectively. 12 Additionally, studies in healthy volunteers indicate that PMs experience enhanced or prolonged b-blockade compared with EM subjects.…”

The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease

“…Also Rau et al showed that the impact of the CYP2D6 genotype on metoprolol plasma concentration persists during long-term treatment. PMs had a 6-fold higher steady-state concentration of metoprolol [2].…”

“…The highest plasma concentration value of metoprolol is reached approximately 2 h after administration of a single dose. Metoprolol is extensively metabolized (oxidation) in the liver by the CYP2D6 isoenzyme of cytochrome P450 [2].…”