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

Abstract

The currently used b-blockers differ in their selectivity for b 1 -and b 2 -adrenergic receptors, lipophilicity and route of elimination. Metoprolol is one of the most commonly used b-blockers in the treatment of ischemic heart disease. Metoprolol is a lipophilic b 1 -selective blocker. This drug is well absorbed from the gastrointestinal tract and undergoes extensive distribution in body tissues; it also passes through the blood-brain barrier. 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].The gene encoding the CYP2D6 enzyme is highly polymorphic. The CYP2D6 oxidation polymorphism has a major impact on the Background:Metoprolol is the one of the most commonly used b-blockers in the treatment of ischemic heart disease and it is extensively metabolized in the liver undergoing oxidation by CYP2D6 isoenzyme of cytochrome P450. Gene encoding the CYP2D6 enzyme is characterized by genetic polymorphism. The CYP2D6 oxidation polymorphism has a major impact on the effectiveness and safety of the treatment. The aim of the study was to evaluate the relationship between plasma concentration of metoprolol and the CYP2D6 genotype in patients with ischemic heart disease. Methods: Fifty patients were interviewed and subsequently enrolled into the study. The patients received metoprolol twice daily at a dose of 50 mg. The blood samples were analyzed for two major defective alleles for CYP2D6 -CYP2D6*4 and CYP2D6*3 -by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Metoprolol concentration in plasma was determined by using the new and unique high-performance liquid chromatography (HPLC) method in the author's own modification with Corona CAD detector (Charged Aerosol Detection). Results: In the test group, genotypes conditioning poor oxidation (PM) occurred in 3 patients (6%), while 47 patients (94%) had genotypes coding for extensive metabolism (EM). Patients with PM genotypes had significantly higher plasma concentrations of metoprolol than the patients with EM genotype (mean 92.25 AE SD 36.78 ng/ml vs. mean 168.22 AE SD 5.61 ng/ml, respectively). Established relationships were statistically significant (NIR test, p = 0.0009). Conclusions: This study demonstrated that the CYP2D6 genotype remains a major determinant of the metoprolol plasma concentrations. The pharmacogenetic effect is likely to have consequences on both, the clinical benefit of metoprolol treatment and adverse drug reactions. The use of Corona CAD detector seems to be a very good alternative method for the determination of metoprolol concentration in plasma.

Bioartificial Liver Device Based on Induced Pluripotent Stem Cell-Derived Hepatocytes

“…We observed that cytochrome p450 genes and transporters were differentially expressed in iHeps, fetal hepatocytes and HepG2. This is not surprising given the variation in CYP gene induction kinetics and CYP polymorphisms (pharmacogenetics) in individuals of different genetic backgrounds that have been shown to affect drug metabolism and clearance [45,46,63,64]. Establishing a repertoire of well-characterized iPSC lines from individuals of diverse genetic backgrounds and/or collecting iPSC lines with genetically engineered CYP genes can be useful for the treatment of the wide range of liver diseases due to drug overdoses or altered CYP metabolic activity.…”