title: ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice.
abstract: Cannabidiol (CBD) is currently being investigated as a novel therapeutic for the treatment of CNS disorders like schizophrenia and epilepsy. ABC transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) mediate pharmacoresistance in these disorders. P-gp and Bcrp are expressed at the blood brain barrier (BBB) and reduce the brain uptake of substrate drugs including various antipsychotics and anticonvulsants. It is therefore important to assess whether CBD is prone to treatment resistance mediated by P-gp and Bcrp. Moreover, it has become common practice in the drug development of CNS agents to screen against ABC transporters to help isolate lead compounds with optimal pharmacokinetic properties. The current study aimed to assess whether P-gp and Bcrp impacts the brain transport of CBD by comparing CBD tissue concentrations in wild-type (WT) mice versus mice devoid of ABC transporter genes. P-gp knockout (Abcb1a/b (-∕-)), Bcrp knockout (Abcg2 (-∕-)), combined P-gp/Bcrp knockout (Abcb1a/b (-∕-) Abcg2 (-∕-)) and WT mice were injected with CBD, before brain and plasma samples were collected at various time-points. CBD results were compared with the positive control risperidone and 9-hydroxy risperidone, antipsychotic drugs that are established ABC transporter substrates. Brain and plasma concentrations of CBD were not greater in P-gp, Bcrp or P-gp/Bcrp knockout mice than WT mice. In comparison, the brain/plasma concentration ratios of risperidone and 9-hydroxy risperidone were profoundly higher in P-gp knockout mice than WT mice. These results suggest that CBD is not a substrate of P-gp or Bcrp and may be free from the complication of reduced brain uptake by these transporters. Such findings provide favorable evidence for the therapeutic development of CBD in the treatment of various CNS disorders.
authors.affiliation: Discipline of Pharmacology, School of Medical Science, University of Sydney , Sydney, NSW , Australia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Brzozowska
authors.affiliation: Discipline of Pharmacology, School of Medical Science, University of Sydney , Sydney, NSW , Australia.
authors.forename: Kong M
authors.initials: KM
authors.lastname: Li
authors.affiliation: Bosch Mass Spectrometry Facility, Bosch Institute, Sydney Medical School, University of Sydney , Sydney, NSW , Australia.
authors.forename: Xiao Suo
authors.initials: XS
authors.lastname: Wang
authors.affiliation: Psychopharmacology Laboratory, School of Psychology, Faculty of Science, University of Sydney , Sydney, NSW , Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Booth
authors.affiliation: The Lambert Initiative of Cannabinoid Therapeutics, The Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia; Psychopharmacology Laboratory, School of Psychology, Faculty of Science, University of Sydney, Sydney, NSW, Australia.
authors.forename: Jordyn
authors.initials: J
authors.lastname: Stuart
authors.affiliation: The Lambert Initiative of Cannabinoid Therapeutics, The Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia; Psychopharmacology Laboratory, School of Psychology, Faculty of Science, University of Sydney, Sydney, NSW, Australia.
authors.forename: Iain S
authors.initials: IS
authors.lastname: McGregor
authors.affiliation: Discipline of Pharmacology, School of Medical Science, University of Sydney, Sydney, NSW, Australia; The Lambert Initiative of Cannabinoid Therapeutics, The Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
authors.forename: Jonathon C
authors.initials: JC
authors.lastname: Arnold
keywords: ABC transporters; Brain disposition; Breast cancer resistance protein; Cannabidiol; P-glycoprotein; Risperidone; Substrate