The relevance of CYP2D6 genetic polymorphism on chronic metoprolol therapy in cardiovascular patients.
OBJECTIVE
CYP2D6 polymorphisms are well described in normal populations but there are few data on its clinical significance. We therefore investigated the influence of CYP2D6 polymorphism on steady-state plasma concentrations and apparent oral clearance of metoprolol in patients with cardiovascular diseases.


METHODS
Ninety-one patients on metoprolol were recruited. Plasma concentrations of metoprolol and alpha-hydroxy metoprolol were measured at 4-h post-dose. CYP2D6 genotyping (*1, *3, *4, *5, *9, *8, *10, *17 and duplication) were performed on the DNA extracted. Ratio of plasma concentrations of metoprolol and alpha-hydroxy metoprolol and the apparent oral clearance of metoprolol were calculated. The influences of CYP2D6 genotypes were investigated.


RESULTS
A 100-fold variation was noted for both plasma concentrations of metoprolol and alpha-hydroxy metoprolol. There was a weak correlation between the total daily doses and plasma concentrations of both. Plasma concentrations were found to be higher in patients with genotypes that predicted lower enzyme activity. One patient homozygous for CYP2D6*4 had the highest metoprolol concentration per unit dose. With an antimode of 10. Two patients were identified as poor metabolizers (PMs) (2.1%; 95% CI: 2.9). The PMs who had a plasma metabolic ratio (pMR) of 37.8 was homozygous CYP2D6*4 whereas the other with pMR 14.5 was genotyped CYP2D6 *4/*10. There was a 36-fold difference between the highest and lowest clearance values. Large overlaps in the clearance values were noted between most of the genotypes.


CONCLUSIONS
Our data suggest that pharmacogenetic measures could be used to design a more individualized metoprolol dosage regimen for patients.
Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Malaysia. isrusli@kb.usm.my
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D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008790:Metoprolol / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic
D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; C029504:alpha-hydroxymetoprolol; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol