The oxidative metabolism of metoprolol in human liver microsomes: inhibition by the selective serotonin reuptake inhibitors.
OBJECTIVE
Biotransformation of metoprolol to alpha-hydroxymetoprolol (HM) and O-demethylmetoprolol (ODM) is mediated by CYP2D6. The selective serotonin reuptake inhibitors (SSRIs) are known to inhibit CYP2D6. The aim was to study in vitro the potential inhibitory effect of SSRIs on metoprolol biotransformation.


METHODS
Using microsomes from two human livers, biotransformation of metoprolol to alpha-hydroxymetoprolol (HM) and O-demethylmetoprolol (ODM) as a function of the concentrations of the SSRIs and of some of their metabolites was studied.


RESULTS
The kinetics of the formation of both metabolites are best described by a biphasic enzyme model. The estimated values of Vmax and kM for the high affinity site are for the alpha-hydroxylation in human liver HL-1 32 pmol mg(-1) min(-1) and 75 micromol x l(-1) respectively, and in human liver HL-9 39 pmol mg(-1) x min(-1) and 70 micromol x l(-1) respectively; for the O-demethylation in HL-1 131 pmol mg(-1) min(-1) and 95 micromol x l(-1) respectively, and in HL-9 145 pmol mg(-1) min(-1) and 94 micromol x l(-1) respectively. Quinidine is for both pathways a potent inhibitor of the high-affinity site, with K(i) values ranging from 0.03 to 0.18 micromol x l(-1). Fluoxetine, norfluoxetine and paroxetine are likewise potent inhibitors, with Ki values ranging from 0.30 to 2.1 micromol x l(-1) fluvoxamine, sertraline, desmethylsertraline, citalopram and desmethylcitalopram are less potent inhibitors, with K(i) values above 10 micromol x l(-1).


CONCLUSIONS
The rank order of the SSRIs for inhibition of metoprolol metabolism is comparable to that reported in the literature for other CYP2D6 substrates, with fluoxetine, norfluoxetine and paroxetine being the most potent. These findings need further investigation to determine their clinical relevance.
Heymans Institute of Pharmacology, University of Gent Medical School, Belgium. frans.belpaire@rug.ac.be
F M
FM
Belpaire
P
P
Wijnant
A
A
Temmerman
B B
BB
Rasmussen
K
K
Brøsen
D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002648:Child; D015283:Citalopram / Q000031:analogs & derivatives / Q000494:pharmacology; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D016666:Fluvoxamine / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008745:Methylation / Q000187:drug effects; D008790:Metoprolol / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D017374:Paroxetine / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D020280:Sertraline
D015057:1-Naphthylamine; D000889:Anti-Arrhythmia Agents; D015283:Citalopram; D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D005473:Fluoxetine; D016666:Fluvoxamine; D008790:Metoprolol; D017374:Paroxetine; D011802:Quinidine; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; C036139:norfluoxetine