Stereoselective distribution of hydroxychloroquine in the rabbit following single and multiple oral doses of the racemate and the separate enantiomers

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Abstract
Hydroxychloroquine (HCQ) stereoselective distribution was investigated in rabbits after 20 mg/kg po of racemic‐HCQ (rac‐HCQ) and 20 mg/kg po of each enantiomer, 97% pure (−)‐(R)‐HCQ and 99% pure (+)‐(S)‐HCQ. Concentrations were 4 to 6 times higher in whole blood than in plasma. Melanin did not affect plasma and whole blood levels since concentrations did not differ between pigmented and nonpigmented animals. After single and multiple doses of the separate enantiomers, only 5–10% of the antipode could be measured, in blood or plasma. Therefore, there was no significant interconversion from one enantiomer into the other. Following rac‐HCQ, plasma (+)‐(S)‐levels always surpassed (−)‐(R)‐ones while in whole blood, (−)‐(R)‐HCQ concentrations were always the highest. When the enantiomers were administered separately, blood concentrations achieved after (−)‐(R)‐HCQ were higher, especially after multiple doses. These observations suggest that (−)‐(R)‐HCQ is preferentially concentrated by cellular components of blood. This enantioselective distribution of HCQ could be secondary to a stereoselective protein binding to plasma proteins, although a more specific binding of (−)‐(R)‐HCQ to blood cells cannot be ruled out. Since in whole blood (−)‐(R)‐HCQ is retained in cellular components, metabolism would favour the more available (+)‐(S)‐enantiomer.