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

Abstract

Introduction: Animal studies suggest that adolescent exposure to Δ⁹-tetrahydrocannabinol (Δ⁹-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 Δ⁹-THC pharmacokinetics in adolescent and adult female mice, which identify significant dissimilarities in distribution and metabolism of Δ⁹-THC between females of these age groups. Materials and Methods: We administered Δ⁹-THC (5 mg/kg, intraperitoneal) to adolescent (37-day old) and young adult (70-day old) female mice and quantified Δ⁹-THC and its first-pass metabolites-11-hydroxy-Δ⁹-THC (11-OH-THC) and 11-nor-9-carboxy-Δ⁹-THC (11-COOH-THC)-in plasma and brain tissue using liquid chromatography/tandem mass spectrometry. Results: Maximal plasma concentrations of Δ⁹-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 Δ⁹-THC metabolites were higher in plasma but lower in brain of adolescent compared to adult female mice. Conclusions: The results identify multiple age-dependent differences in the pharmacokinetic properties of Δ⁹-THC in female mice, which might influence the pharmacological response to the drug.

Keywords: cannabis; liquid chromatography/tandem mass spectrometry (LC-MS/MS); pharmacokinetics; Δ9-Tetrahydrocannabinol.

FIG. 1.

Plasma (top panels) and brain (bottom panels) concentrations of Δ⁹-THC (A, C) and 11-OH-THC (B, D) in adolescent (PND 37, ●) and adult (PND 70, ■) female C57BL/6 mice. Symbols represent mean ± SEM, n = 3 or 4 animals per data point, outlier removed using Grubb’s test for outliers,*p < 0.05, ***p < 0.001, two-way ANOVA. ANOVA, analysis of variance; PND, postnatal day; Δ⁹-THC, Δ⁹-tetrahydrocannabinol.