ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice

Natalia Brzozowska; Kong M Li; Xiao Suo Wang; Jessica Booth; Jordyn Stuart; Iain S McGregor; Jonathon C Arnold

doi:10.7717/peerj.2081

ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice

PeerJ. 2016 May 26:4:e2081. doi: 10.7717/peerj.2081. eCollection 2016.

Authors

Natalia Brzozowska¹, Kong M Li¹, Xiao Suo Wang², Jessica Booth³, Jordyn Stuart⁴, Iain S McGregor⁴, Jonathon C Arnold⁵

Affiliations

¹ Discipline of Pharmacology, School of Medical Science, University of Sydney , Sydney, NSW , Australia.
² Bosch Mass Spectrometry Facility, Bosch Institute, Sydney Medical School, University of Sydney , Sydney, NSW , Australia.
³ Psychopharmacology Laboratory, School of Psychology, Faculty of Science, University of Sydney , Sydney, NSW , Australia.
⁴ 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.
⁵ 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.

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.

Keywords: ABC transporters; Brain disposition; Breast cancer resistance protein; Cannabidiol; P-glycoprotein; Risperidone; Substrate.

Grants and funding

This work was supported by a University of Sydney Bridging Grant and a Bosch Translational Grant-in-Aid to JCA. JCA was also supported by the Brain & Behaviour Research Foundation (formerly National Alliance for Research on Schizophrenia and Depression: Young Investigator Award). NB is supported by an Australian Postgraduate Award Scholarship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.