Stereoselective disposition of hydroxychloroquine and its metabolite in rats.

Racemic hydroxychloroquine-sulfate (HCQ-sulfate) was administered to rats orally. Groups of 9 male and 9 female rats received doses of 0, 8, 16, or 24 mg/kg/day for 6 weeks, followed by a reduction of the higher doses to 8 mg/kg/day for the duration of the study. Whole blood samples were collected at 0, 3, 6, 8, and 10 weeks, and eleven tissues were harvested after the tenth week. The concentrations and enantiomer ratios of the parent drug and three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ), were determined. The highest concentration of HCQ was found in the intestinal smooth muscle, and the lowest in the brain and adipose tissue. The highest concentrations of the metabolites were found in the liver, adrenals, and lung tissue. The metabolism of HCQ in the rats was found to be stereoselective with R/S > 1 for the drug and < 1 for the metabolites. Gender-specific differences in the proportions of the drug and its metabolites and their enantiomers in blood and tissue were found. Varying dosages appeared to have only a temporary influence on blood concentrations and not to effect the enantiomer ratios in blood. Only a limited number of tissues exhibited significant differences between dose groups. There were no observed differences in enantiomer ratios among the blood collection times.

Steady-state pharmacokinetics of hydroxychloroquine in rheumatoid arthritis patients.

Steady-state pharmacokinetics of hydroxychloroquine (HC) sulfate (Plaquenil) were studied in five volunteers with rheumatoid arthritis who had taken 6 mg/kg/d of the drug for at least six months. Blood samples were drawn at 0, 1, 2, 4, 6, 8, 12, and 24 hours following an oral dose. Both whole blood and plasma were assayed by an HPLC method for HC and its metabolites desethylhydroxychloroquine, desethylchloroquine, and didesethylchloroquine. A 24-hour urine collection was obtained and assayed for the same compounds. The pharmacokinetics of HC and its metabolites conformed to the model predicted by single-dose studies. During the 24-hour period the absorption phase and both early and late distribution phases were seen. Variation in mean maximum/minimum concentration was 40 percent. Renal clearance accounted for only 16 percent of unchanged HC (22 percent of total drug and metabolites) and did not correlate with creatinine clearance.