Comparative pharmacokinetics of Δ⁹-tetrahydrocannabinol in adolescent and adult male mice

We investigated the pharmacokinetic properties of Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive constituent of cannabis, in adolescent and adult male mice. The drug was administered at logarithmically ascending doses (0.5, 1.6, and 5 mg/kg, i.p.) to pubertal adolescent (37-day-old) and adult (70- day-old) mice. Δ9-THC and its first-pass metabolites - 11- hydroxy-Δ9-THC and 11-nor-9-carboxy-Δ9-THC (11-COOHTHC) - were quantified in plasma, brain, and white adipose tissue (WAT) using a validated isotope-dilution liquid chromatography/ tandem mass spectrometry assay. Δ9-THC (5 mg/kg) reached 50% higher circulating concentration in adolescent mice than in adult mice. A similar age-dependent difference was observed in WAT. Conversely, 40%-60% lower brain concentrations and brain-to-plasma ratios for Δ9-THC and 50%- 70% higher brain concentrations for Δ9-THC metabolites were measured in adolescent animals relative to adult animals. Liver microsomes from adolescent mice converted Δ9-THC into 11- COOH-THC twice as fast as adult microsomes. Moreover, the brains of adolescent mice contained higher mRNA levels of the multidrug transporter breast cancer resistance protein, which may extrude Δ9-THC from the brain, and higher mRNA levels of claudin-5, a protein that contributes to blood-brain barrier integrity. Finally, administration of Δ9-THC (5 mg/kg) reduced spontaneous locomotor activity in adult, but not adolescent, animals. The results reveal the existence of multiple differences in the distribution and metabolism of Δ9-THC between adolescent and adult male mice, which might influence the pharmacological response to the drug. SIGNIFICANCE STATEMENT Animal studies suggest that adolescent exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the intoxicating constituent of cannabis, causes persistent changes in brain function. These studies generally overlook the impact that age-dependent changes in the distribution and metabolism of the drug might exert on its pharmacological effects. This report provides a comparative analysis of the pharmacokinetic properties of Δ9-THC in adolescent and adult male mice and outlines multiple functionally significant dissimilarities in the distribution and metabolism of Δ9-THC between these two age groups.