Influence of hydroxychloroquine on the bioavailability of oral metoprolol.
OBJECTIVE
Hydroxychloroquine (HCQ) is used widely in the treatment of chronic inflammatory diseases such as rheumatoid arthritis. Since there is great interindividual variability in the pharmacokinetics of HCQ and chloroquine is a potent inhibitor of CYP2D6-catalysed pathways in vitro, we wished to study the interaction of HCQ with CYP2D6-mediated metabolism of other drugs in vivo.


METHODS
Metoprolol and dextromethorphan (DM) were selected as probe drugs because they are well-studied and widely used test substrates of CYP2D6. In this randomized, double-blind crossover study, seven healthy volunteers with extensive metabolizer phenotype for CYP2D6 ingested either 400 mg hydroxychloroquine or placebo daily for 8 days after which single oral dose pharmacokinetics of metoprolol were investigated. Dextromethorphan metabolic ratio (DM-MR) was also determined at baseline and after the ingestion of HCQ or placebo.


RESULTS
Concomitant administration of HCQ increased the bioavailability of metoprolol, as indicated by significant increases in the area under the plasma concentration-time curve (65 +/- 4.6%) and maximal plasma concentrations (72 +/- 6.9%) of metoprolol. While the DM-MR values were not significantly changed, the phenotypic classification of one individual, who was heterozygous for a mutant CYP2D6 allele, was converted to a poor metabolizer by HCQ administration.


CONCLUSIONS
HCQ inhibits metoprolol metabolism most probably by inhibiting its biotransformation by CYP2D6. The inhibitory effect of HCQ on dextromethorphan metabolism was not apparent when DM-MR was used as an indicator, except in an individual with limited CYP2D6 capacity.
Somer
M
M
Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland.
Kallio
J
J
Pesonen
U
U
Pyykkö
K
K
Huupponen
R
R
Scheinin
M
M
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000328:Adult; D000962:Antimalarials / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan / Q000652:urine; D004311:Double-Blind Method; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology*; D008297:Male; D008790:Metoprolol / Q000493:pharmacokinetics*
D000319:Adrenergic beta-Antagonists; D000962:Antimalarials; D018501:Antirheumatic Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D006886:Hydroxychloroquine; D003915:Dextromethorphan; D008790:Metoprolol