P-glycoprotein (P-gp) is a transporter molecule that is used by the body in absorbing and depositing many different endogenous (from the body) and exogenous (from outside the body) chemicals. It is powered by ATP, the energy unit of life. This is a fundamental process and we would all die without it.
However, the protein is one of the reasons that many drugs never get past the blood-brain barrier, limiting their uses. With further understanding of P-gp, we can potentially develop more effective drugs for all manner of diseases and conditions, and potentially make existing drugs more effective.
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A cannabinoid found in high concentrations in the cannabis plant is cannabidiol, or CBD. It was the most effective P-gp inhibitor of the four cannabinoids:
That were assayed in this study. The other three did not show much effect. When CBD and P-gp interactions were investigated further, it was found that higher concentrations of CBD significantly inhibited P-gp-mediated drug transport. This adds to our understanding of this process and could be useful for assessing and developing drugs that rely on P-gp absorption and deposition.
Cannabidiol is a chemical that is getting a lot of attention of late. It is an effective anti-inflammatory, there is evidence it has tumour growth-slowing effects and is an effective antiemetic for chemotherapy. In this study, it was found that CBD successfully inhibited P-gp deposition and absorption. The implications are substantial. Many chemotherapies are limited by P-gp facilitated reactions involving something called the multidrug resistance protein (MDR).
A proposed course of action is to investigate whether CBD can be used as a P-gp inhibitor like some other drugs have been proven to do. The advantage of using CBD is that it is highly tolerable and has a good safety profile, as well as not producing any psychoactivity. Potentially, CBD could be used alongside anticancer chemotherapy to increase its efficacy, as well as potentially reduce some of the nausea caused by the chemotherapy.
THC, THC-COOH, and CBN were tested in the same way but showed no significant effect. Cannabidiol is known to behave differently from THC, which binds directly to CB1 receptors. However, it is unclear how or why this happens in this case.
However, the pharmacokinetics and pharmacodynamics (how they work, essentially) of these cannabinoids are affected by P-gp action. They are proposed as P-gp substrates or chemicals on which P-gp acts as an enzyme. Further research will explore these interactions.
The authors give no explanation of how CBD mediates its P-gp inhibitory effects. CBD has many molecular targets around the body, including CB2, HT, and TRPV receptors. The chains of reactions that mediate inflammation, absorption, and deposition are complex and not properly unravelled yet. However, this paper adds significantly to the knowledge of these vital processes and establishes the role of the endocannabinoid system therein.
A tiny glimpse into the complicated world of absorption and deposition using P-gp, this study links the endocannabinoid system and P-gp, generating for the first time data on the effects of cannabinoids on P-gp and proposing the effect of P-gp on some cannabinoids. CBD was an effective inhibitor, which could be very useful for chemotherapies.