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.

Cannabinoids, Blood–Brain Barrier, and Brain Disposition

“…In humans, polymorphism of phenotypes for the gene Multi-Drug Resistance 1 affects the development of dependence from cannabis. A more thorough investigation could be useful to increase knowledge on discrepancy observed in individual responses to THC effects [94].…”

“…Results of the study showed that CBD plasma concentrations were not higher in P-gp, Bcrp, or P-gp/Bcrp knockout mice compared with wild type mice. Therefore, since it has been suggested that CBD is not a substrate of P-gp or Bcrp and can represent a promising drug to be used for CNS diseases [94]. If we look at CBD as a therapeutic strategy for CNS diseases, and since P-gp or Bcrp do not obstacle the brain entry of CBD, as consequence, CBD may be free from the development of drug resistance when it is played by these ABC transporters.…”

Is cannabidiol a drug acting on unconventional targets to control drug‐resistant epilepsy?

“…It is important to mention that CBD is not a substrate of P‐glycoprotein. In mice, experiments revealed that the overexpression of this transporter at BBB does not limit the brain uptake of CBD . This condition associated with the inhibitory effect of P‐glycoprotein at BBB plus its anticonvulsant and neuroprotective effects suggests that CBD can be an attractive adjunctive therapy to control drug‐resistant epilepsy.…”

“…In mice, experiments revealed that the overexpression of this transporter at BBB does not limit the brain uptake of CBD. 119 This condition associated with the inhibitory effect of P-glycoprotein at BBB plus its anticonvulsant and neuroprotective effects suggests that CBD can be an attractive adjunctive therapy to control drug-resistant epilepsy. However, further studies are necessary to demonstrate that the exposure to CBD blocks the activity of P-glycoprotein and/or reverts its overexpression in neurons and astrocytes in brain tissue obtained from subjects with drug-resistant epilepsy.…”

Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor

“…Polyspecific ABC transporters, including P-glycoprotein (ABCB1), MRP1 (ABCC1), and breast cancer resistance protein (BCRP; ABCG2), are associated with MDR. 4,5 ABCG2 was discovered in the multidrug-resistant breast cancer cell line MCF-7/AdrVp. 6,7 This protein is expressed in various organs with barrier functions and numerous types of cancer.…”