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

Author:

Brzozowska Natalia1,Li Kong M.1,Wang Xiao Suo2,Booth Jessica3,Stuart Jordyn43,McGregor Iain S.43,Arnold Jonathon C.14

Affiliation:

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

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.

Funder

University of Sydney Bridging Grant

Bosch Translational Grant-in-Aid

Brain & Behaviour Research Foundation

Australian Postgraduate Award Scholarship

Publisher

PeerJ

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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