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

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.

Enantioselective disposition of hydroxychloroquine after a single oral dose of the racemate to healthy subjects [see comments]

“…The higher R(-)-HCQ concentrations are unlikely to result from the conversion of the S(+) enantiomer. In the rabbit, where the R/S ratios of HCQ blood concentrations are similar to those found in humans, the oral administration of either the racemate or the pure enantiomers also led to higher R(-)-HCQ blood concentrations, and there was no interconversion between enantiomers [13].…”

“…However, considering only plasma protein binding would negate the involvement of any binding to blood cells. This could be critical since HCQ appears to be accumulating not only in erythrocytes, but also in some white blood cells [13,15]. It would be even more clinically relevant if these cells participate, directly or indirectly, in the pharmacological effects of the drug.…”

Enantioselective analysis of the metabolites of hydroxychloroquine and application to an in vitro metabolic study

“…The blood concentrations of (+)-(S)-DCQ and (+)-(S)-DHCQ exceeded those of the (−)-(R)-metabolites [6]. In rabbits, the R/S ratios of HCQ blood concentrations are similar to those found in humans [8]. Wei et al [4] investigated the stereoselective disposition of HCQ and its metabolites in blood and tissues of rats.…”

Significantly enhanced tumor cellular and lysosomal hydroxychloroquine delivery by smart liposomes for optimal autophagy inhibition and improved antitumor efficiency with liposomal doxorubicin

“…[9][10][11][12] However, a major challenge with HCQ is achieving a sufficiently high concentration within target tissue to inhibit autophagy effectively, [13][14][15] primarily because the drug shows nonselective distribution in vivo. [16][17][18][19] In addition, the high metabolic rate of tumors often leads to an acidic tumor microenvironment. 20 Tumor cells have thus evolved the ability to function in a more acidic environment than normal cells, and counteracting tumor acidic pH is being evaluated as a feasible therapeutic strategy in clinical settings using different approaches.…”