pgp - publications

Predict more pgp - ligand interactions now!

1. PLoS One. 2012;7(4):e35937. Epub 2012 Apr 20.

Enhanced brain disposition and effects of δ(9)-tetrahydrocannabinol in
p-glycoprotein and breast cancer resistance protein knockout mice.

Spiro AS, Wong A, Boucher AA, Arnold JC.

Discipline of Pharmacology, University of Sydney, Sydney, New South Wales,

The ABC transporters P-glycoprotein (P-gp, Abcb1) and breast cancer resistance
protein (Bcrp, Abcg2) regulate the CNS disposition of many drugs. The main
psychoactive constituent of cannabis Δ(9)-tetrahydrocannabinol (THC) has affinity
for P-gp and Bcrp, however it is unknown whether these transporters modulate the
brain accumulation of THC and its functional effects on the CNS. Here we aim to
show that mice devoid of Abcb1 and Abcg2 retain higher brain THC levels and are
more sensitive to cannabinoid-induced hypothermia than wild-type (WT) mice.
Abcb1a/b (-/-), Abcg2 (-/-) and wild-type (WT) mice were injected with THC before
brain and blood were collected and THC concentrations determined. Another cohort
of mice was examined for THC-induced hypothermia by measuring rectal body
temperature. Brain THC concentrations were higher in both Abcb1a/b (-/-) and
Abcg2 (-/-) mice than WT mice. ABC transporter knockout mice exhibited delayed
elimination of THC from the brain with the effect being more prominent in Abcg2
(-/-) mice. ABC transporter knockout mice were more sensitive to THC-induced
hypothermia compared to WT mice. These results show P-gp and Bcrp prolong the
brain disposition and hypothermic effects of THC and offer a novel mechanism for
both genetic vulnerability to the psychoactive effects of cannabis and drug
interactions between CNS therapies and cannabis.

PMCID: PMC3335007
PMID: 22536451 [PubMed - in process]