PT  - JOURNAL ARTICLE
AU  - Alexa Torrens
AU  - Valentina Vozella
AU  - Hannah Huff
AU  - Brandon McNeil
AU  - Faizy Ahmed
AU  - Andrea Ghidini
AU  - Stephen V Mahler
AU  - Marilyn A Huestis
AU  - Aditi Das
AU  - Daniele Piomelli
TI  - Comparative Pharmacokinetics of Δ<sup>9</sup>-Tetrahydrocannabinol in Adolescent and Adult Male Mice
AID  - 10.1124/jpet.120.265892
DP  - 2020 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.120.265892
4099  - http://jpet.aspetjournals.org/content/early/2020/04/28/jpet.120.265892.short
4100  - http://jpet.aspetjournals.org/content/early/2020/04/28/jpet.120.265892.full
AB  - 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, intraperitoneal) to pubertal adolescent (37-day old) and adult (70-day old) mice. Δ9-THC and its first-pass metabolites - 11-hydroxy-Δ9-THC (11-OH-THC) and 11-nor-9-carboxy-Δ9-THC (11-COOH-THC) - were quantified in plasma, brain and white adipose tissue (WAT) using a validated isotope-dilution liquid chromatography/tandem mass spectrometry assay. Δ9-THC administration (5 mg/kg) reached 50% higher circulating concentration in adolescent than in adult mice. A similar age-dependent difference was observed in WAT. Conversely, 40% to 60% lower brain concentrations and brain-to-plasma ratios for Δ9-THC and 50% to 70% higher brain concentrations for Δ9-THC metabolites were measured in adolescent relative to adult animals. Liver microsomes from adolescent mice converted Δ9-THC into 11-COOH-THC twice as fast as adult microsomes. Moreover, the brain of adolescent mice contained higher mRNA levels of the multi-drug transporter Abcg2, which may extrude Δ9-THC from the brain, and of claudin-5, a protein that contributes to blood-brain barrier integrity. The results reveal the existence of multiple dissimilarities in the distribution and metabolism of Δ9-THC between adolescent and adult male mice, which might influence wide-ranging pharmacological responses to the drug.SIGNIFICANCE STATEMENT Animal studies suggest that adolescent exposure to Δ9-tetrahydrocannabinol, the intoxicating constituent of cannabis, causes persistent changes in brain function. These studies generally overlooked 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.