ABSTRACT:The effect of protein calorie malnutrition (PCM) on the pharmacokinetics of ketamine (KET) enantiomers has been investigated. Six control and six PCM rats were administered 85 mg/kg racemic KET by intramuscular injection, and plasma concentrations of (S)-and (R)-KET, norketamine (NKET), and 5,6-dehydronorketamine (DNK) were measured using enantioselective gas chromatography. Pharmacokinetic profiles were analyzed using standard noncompartmental and compartmental modeling methods. The volumes of distribution were similar between control and PCM rats for (S)-and (R)-KET. However, total clearance of both KET enantiomers was decreased, resulting in an increase in systemic exposure (p < 0.05). The KET absorption rate was also increased in PCM rats. A decrease in the clearance of both NKET enantiomers led to a significant increase in exposure in PCM rats (p < 0.005), and modeling results could not exclude the possibility that PCM induced an increase in the fraction of KET following the NKET pathway, which may further contribute to this increase in exposure. An increase in exposure to DNK enantiomers was also evident in PCM animals compared with controls [p < 0.005 (DNK1); N.S. (DNK2)], which was in concordance with the decrease in apparent clearance values. These results show that PCM significantly alters the pharmacokinetics of KET and several of its metabolites.

The disposition of the enantiomers of hydroxychloroquine (HCQ) and its major metabolites in ocular tissues of rabbits has been studied. Both albino, New Zealand White (NZW), and pigmented animals were administered daily oral doses of rac-HCQ, (S)-HCQ or (R)-HCQ (20 mg/kg) over 1, 6, or 8 day periods or for 8 days followed by a 7-day washout period. At the end of the study periods, plasma and whole blood samples were collected and the rabbits were sacrificed. The eyes were collected, the aqueous humor removed with a syringe, and the eyes separated into the cornea, lens, vitreous body, iris, choroid-retina, sclera, and conjunctiva. The concentrations of (R)-HCQ, (S)-HCQ, and their respective metabolites were determined using a validated enantioselective liquid chromatographic assay. The data from these studies indicate that HCQ accumulated in both pigmented and nonpigmented ocular tissues. In the pigmented tissues, HCQ and its metabolites were bound to melanin and the binding was not enantiospecific. In the nonpigmented tissues and in the iris and retina-choroid of the NZW rabbits, the accumulation appeared to be the result of a reversible and enantioselective binding of HCQ and its metabolites to an unidentified biopolymer present in these ocular tissues.

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.

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