Disposition of the enantiomers of hydroxychloroquine in patients with rheumatoid arthritis following multiple doses of the racemate

In eight patients with rheumatoid arthritis receiving racemic hydroxychloroquine, blood and urine concentrations of the enantiomers of hydroxychloroquine and its major metabolites were measured each month over the first 6 months of therapy. Plasma concentrations of hydroxychloroquine enantiomers were measured in five of these patients. In all patients, the blood concentration of (R)-hydroxychloroquine exceeded that of the (S)-enantiomer, the mean (R)/(S) ratio being 2.2 (range 1.6-2.9). A similar excess of (R)-hydroxychloroquine was found in the plasma, the mean (R)/(S) ratio being 1.6 (range 1.2-1.9). The mean enantiomer blood concentration ratio (R)/(S) for the metabolite desethylhydroxychloroquine was 0.45 (range 0.34-0.58) and for desethylchloroquine it was 0.56 (range 0.35-0.86) suggesting stereoselective metabolism of hydroxychloroquine. (S)-hydroxychloroquine had a mean (+/- s.d.) renal clearance from blood of 41 +/- 11 ml min-1, approximately twice that of (R)-hydroxychloroquine. The predicted unbound renal clearance was also higher for (S)-hydroxychloroquine. The clinical implications of enantioselective disposition of hydroxychloroquine are currently not known.