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

Alexa Torrens, Valentina Vozella, Hannah Huff, Brandon McNeil, Faizy Ahmed, Andrea Ghidini, Stephen V. Mahler, Marilyn A. Huestis, Aditi Das, Daniele Piomelli

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)151-160
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume374
Issue number1
DOIs
StatePublished - Jul 1 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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