Influence of hydroxychloroquine on the bioavailability of oral metoprolol

Aims Hydroxychloroquine (HCQ) is used widely in the treatment of chronic in flammatory diseases such as rheumatoid arthritis. Since there is great inte rindividual 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 v ivo. Methods Metoprolol and dextromethorphan (DM) were selected as probe drugs b ecause they are well-studied and widely used test substrates of CYP2D6. In this randomized, double-blind crossover study, seven healthy volunteers wit h extensive metabolizer phenotype for CYP2D6 ingested either 400 mg hydroxy chloroquine or placebo daily for 8 days after which single oral dose pharma cokinetics of metoprolol were investigated. Dextromethorphan metabolic rati o (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 pla sma concentration-time curve (65 +/- 4.6%) and maximal plasma concentration s (72 +/- 6.9%) of metoprolol. While the DM-MR values were not significantl y changed, the phenotypic classification of one individual, who was heteroz ygous for a mutant CYP2D6 allele, was converted to a poor metabolizer by HC Q administration. Conclusions HCQ inhibits metoprolol metabolism most probably by inhibiting its biotransformation by CYP2D6. The inhibitory effect of HCQ on dextrometh orphan metabolism was not apparent when DM-MR was used as an indicator, exc ept in an individual with limited CYP2D6 capacity.