Abstract
Recent work from our group and others has revealed a higher sensitivity of female rodents to the antidepressant-like effects of N-methyl d-aspartate receptor (NMDAR) antagonist, ketamine, strongly influenced by circulating estrogen (E2) and progesterone (P4) levels. However, in the absence of any preclinical studies of pharmacokinetic sex differences using low-dose ketamine in rats, it is unclear whether the effects of sex and hormonal milieu on ketamine's behavioral actions are influenced by differences in ketamine metabolism between male and female rats. Therefore, this work examined whether or not sex and hormonal status effect ketamine metabolism and distribution in male and female rats using a low antidepressant-like dose selectively-effective in females. Intact male rats and female rats in either diestrus (low E2, P4) or proestrus (high E2, P4) were administered low-dose ketamine, and their plasma and brains collected to analyze levels of ketamine and its metabolites, norketamine (NK) and dehydronorketamine (DHNK). Females exhibited greater concentrations of ketamine and NK over the first 30 minutes following treatment in both the brain and plasma, largely accounted for by slower clearance rates and longer half-lives. Interestingly, despite the impact of ovarian hormones on behavioral sensitivity to ketamine, no appreciable differences in pharmacokinetic parameters existed between proestrus and diestrus female rats. This work is the first to demonstrate sex differences in ketamine pharmacokinetics in rats, and suggests that while sex differences in metabolism may influence the amount of ketamine and NK reaching target areas in the brain, the impact of circulating hormone levels here is negligible.
- The American Society for Pharmacology and Experimental Therapeutics