Biotransformation via a hydrolytic pathway is the major route of endocannabinoid metabolism and the deactivation of substrates is characteristic, in contrast to the minor oxidative pathway via CYP involved in the bioactivation reactions. Phytocannabinoids are extensively metabolized by CYPs. The enzymes CYP2C9, CYP2C19, and CYP3A4 catalyze most of their hydroxylations. Similarly, CYP represents a major metabolic pathway for both synthetic cannabinoids used therapeutically and drugs that are abused. In vitro experiments document the mostly CYP inhibitory activity of the major phytocannabinoids, with cannabidiol as the most potent inhibitor of many CYPs. The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance remains unclear. The direct activation/inhibition of nuclear receptors in the liver cells by cannabinoids may result in a change of CYP expression and activity. Finally, we hypothesize the interplay of central cannabinoid receptors with numerous nervous systems, resulting in a hormone-mediated signal towards nuclear receptors in hepatocytes.
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