Effects of protein calorie malnutrition on the pharmacokinetics of ketamine in rats

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.