Comparative Pharmacokinetics of Δ9-Tetrahydrocannabinol in Adolescent and Adult Female Mice.

Animal studies suggest that adolescent exposure to Δ-tetrahydrocannabinol (Δ-THC), the intoxicating constituent of cannabis, causes lasting functional alterations in brain and other organs. Those studies often neglect the impact that age- and sex-dependent differences in the distribution and metabolism of the drug might exert on its pharmacological effects. Here, we provide a comparative analysis of Δ-THC pharmacokinetics in adolescent and adult female mice, which identify significant dissimilarities in distribution and metabolism of Δ-THC between females of these age groups. We administered Δ-THC (5 mg/kg, intraperitoneal) to adolescent (37-day old) and young adult (70-day old) female mice and quantified Δ-THC and its first-pass metabolites-11-hydroxy-Δ-THC (11-OH-THC) and 11-nor-9-carboxy-Δ-THC (11-COOH-THC)-in plasma and brain tissue using liquid chromatography/tandem mass spectrometry. Maximal plasma concentrations of Δ-THC were 8 times higher in adolescent than adult female mice. Conversely, brain concentrations and brain-to-plasma ratios were 25-50% higher in adults than adolescents. Concentrations of Δ-THC metabolites were higher in plasma but lower in brain of adolescent compared to adult female mice. The results identify multiple age-dependent differences in the pharmacokinetic properties of Δ-THC in female mice, which might influence the pharmacological response to the drug.