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

Abstract

We investigated the pharmacokinetic properties of D 9 -tetrahydrocannabinol (D 9 -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 (70day-old) mice. D 9 -THC and its first-pass metabolites-11hydroxy-D 9 -THC and 11-nor-9-carboxy-D 9 -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. D 9 -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 D 9 -THC and 50%-70% higher brain concentrations for D 9 -THC metabolites were measured in adolescent animals relative to adult animals. Liver microsomes from adolescent mice converted D 9 -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 D 9 -THC from the brain, and higher mRNA levels of claudin-5, a protein that contributes to blood-brain barrier integrity. Finally, administration of D 9 -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 D 9 -THC between adolescent and adult male mice, which might influence the pharmacological response to the drug. SIGNIFICANCE STATEMENTAnimal studies suggest that adolescent exposure to D 9 -tetrahydrocannabinol (D 9 -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 D 9 -THC in adolescent and adult male mice and outlines multiple functionally significant dissimilarities in the distribution and metabolism of D 9 -THC between these two age groups.

Effects of Chronic Exposure to Low-Dose delta-9-Tetrahydrocannabinol in Adolescence and Adulthood on Serotonin/Norepinephrine Neurotransmission and Emotional Behavior

“…Importantly, CB1Rs play a critical role in neuronal development due to their ability to modulate the release of neurotransmitters and expression, establishment of synaptic connection ( Kano et al, 2009 ), and epigenetic regulation ( Prini et al, 2018 ). The pharmacological exogenous manipulation of the endocannabinoid system by THC led to changes in neuronal development and homeostasis, pointing out the role of the endogenous cannabinoid system in neurodevelopment ( Viveros et al, 2012 ).…”

Pharmacokinetics and Central Accumulation of Delta-9-Tetrahydrocannabinol (THC) and its Bioactive Metabolites Are Influenced by Route of Administration and Sex

“…Whereas, plasma concentrations of THC-COOH were highest at 30, 60, 90 and 240 min compared to 15 min, reaching average peak levels of ~60 ng/mL, about 9 times higher than inhalation levels. Along these lines, previous studies have also shown peak THC-COOH concentrations at later timepoints (60-120 min) following injection in rats (Torrens et al, 2020) and inhalation in humans (Huestis et al, 1992). Further, given that plasma 11-OH-THC concentrations were higher following injection, and 11-OH-THC is the metabolic precursor of THC-COOH, it is not surprising that THC-COOH follows the same pattern.…”

“…Rodent studies utilizing THC injections allow for control over both dose and timing; however, peak plasma THC concentrations are found at a slightly later timepoint following administration than with respect to inhalation (Javadi-Paydar et al, 2017; Nguyen et al, 2016; Taffe et al, 2020; Torrens et al, 2020). Further, clearance of THC from plasma following IP injections is much slower, with concentrations still roughly 65% of peak at 60 min and 50% at 120 min (Torrens et al, 2020).…”

“…Rodent studies utilizing THC injections allow for control over both dose and timing; however, peak plasma THC concentrations are found at a slightly later timepoint following administration than with respect to inhalation (Javadi-Paydar et al, 2017; Nguyen et al, 2016; Taffe et al, 2020; Torrens et al, 2020). Further, clearance of THC from plasma following IP injections is much slower, with concentrations still roughly 65% of peak at 60 min and 50% at 120 min (Torrens et al, 2020). Rodent studies employing IP injections also utilize a wide range of dosages (3 to 20 mg/kg) producing an extensive span of peak plasma THC concentrations from 40-200 ng/mL (Javadi-Paydar et al, 2017; Nguyen et al, 2016; Taffe et al, 2020; Torrens et al, 2020), suggesting that they are comparable to the range seen in humans following cannabis use.…”

“…Further, clearance of THC from plasma following IP injections is much slower, with concentrations still roughly 65% of peak at 60 min and 50% at 120 min (Torrens et al, 2020). Rodent studies employing IP injections also utilize a wide range of dosages (3 to 20 mg/kg) producing an extensive span of peak plasma THC concentrations from 40-200 ng/mL (Javadi-Paydar et al, 2017; Nguyen et al, 2016; Taffe et al, 2020; Torrens et al, 2020), suggesting that they are comparable to the range seen in humans following cannabis use. Interestingly, brain THC concentrations following IP administration increase over time, peaking at 60-120 min following initial administration (Torrens et al, 2020).…”