The use of a whole plant cannabis extract, containing <span style='font-family:Symbol'>D<sup>9</sup>-tetrahydrocannabinol (THC) and cannabidiol (CBD) as the principal constituents, showed statistically significant improvements in the management of multiple sclerosis. Inhibition studies (e.g. IC<sub>50</sub> and K<sub>i</sub> determinations) using phenotyped human liver microsomes and cDNA expressed human P450s (Supersomes<span style='font-family:Symbol'>â demonstrated that CBD competitively inhibits the principal P450s involved in the THC biotransformation, CYP2C9 (K<sub>i</sub> = 0.5 <span style='font-family:Symbol'>mM), CYP2C19) (K<sub>i</sub> = 0.4 <span style='font-family:Symbol'>mM) and CYP3A4 (K<sub>i</sub> = 0.07 <span style='font-family:Symbol'>mM. CBD inhibition of CYP3A4 was mechanism-based, which suggests that a CBD metabolite (e.g. CBD-hydroxyquinone) is involved in CYP3A4 inhibition. CBD differentially induced rat P450s, whereas THC had no discernible effects on rat P450s. CBD significantly increased CYP1A2 protein at 150 mg kg<sup>-1</sup>, but showed no change in mRNA expression. In addition, CYP1A-dependent activity was inhibited by < 80 % by CBD. These results suggest that CBD may bind tightly to and modify the CYP1A2 active site, thereby stabilising the protein but preventing substrate interaction. The significant increase in CYP2B1 mRNA implies that CBD transcriptionally regulates CYP2B, perhaps by activating CAR or through “cross-talk” by PXR. The 4-fold increase in CYP3A23 mRNA level suggests that CBD may be a weak ligand for PXR or that CBD is acting via CAR, which can also bind to response elements on the CYP3A23 gene. CBD is a potent inhibitor of P450-catalysed THC metabolism <i>in vitro</i> however pharmacokinetic modelling predicted that the therapeutic level of CBD (low nM range) after sublingual co-administration of THC and CBD (10 mg of each) was insufficient to inhibit THC metabolism of other human volunteers. This does not rule out the potential for CBD to inhibit the metabolism of other co-administered drugs <i>in vivo</i>. CBD may also induce the human orthologues of rat P450s, mainly CYP2B6 and CYP3A4, following extended periods of administration at high doses.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:415480 |
| Date | January 2004 |
| Creators | McArdle, Elizabeth Karen |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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