Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review

Abstract

Exogenous cannabinoids are structurally and pharmacologically diverse compounds that are widely used. The purpose of this systematic review is to summarize the data characterizing the potential for these compounds to act as substrates, inhibitors, or inducers of human drug metabolizing enzymes, with the aim of clarifying the significance of these properties in clinical care and drug interactions. In vitro data were identified that characterize cytochrome P-450 (CYP-450) enzymes as potential significant contributors to the primary metabolism of several exogenous cannabinoids: tetrahydrocannabinol (THC; CYPs 2C9, 3A4); cannabidiol (CBD; CYPs 2C19, 3A4); cannabinol (CBN; CYPs 2C9, 3A4); JWH-018 (CYPs 1A2, 2C9); and AM2201 (CYPs 1A2, 2C9). CYP-450 enzymes may also contribute to the secondary metabolism of THC, and UDP-glucuronosyltransferases have been identified as capable of catalyzing both primary (CBD, CBN) and secondary (THC, JWH-018, JWH-073) cannabinoid metabolism. Clinical pharmacogenetic data further support CYP2C9 as a significant contributor to THC metabolism, and a pharmacokinetic interaction study using ketoconazole with oromucosal cannabis extract further supports CYP3A4 as a significant metabolic pathway for THC and CBD. However, the absence of interaction between CBD from oromucosal cannabis extract with omeprazole suggests a less significant role of CYP2C19 in CBD metabolism. Studies of THC, CBD, and CBN inhibition and induction of major human CYP-450 isoforms generally reflect a low risk of clinically significant drug interactions with most use, but specific human data are lacking. Smoked cannabis herb (marijuana) likely induces CYP1A2 mediated theophylline metabolism, although the role of cannabinoids specifically in eliciting this effect is questionable.

Cannabinoids and Epilepsy

“…Both Δ9-THC and CBD can inhibit CYP-450 metabolic activity, particularly the CYP2C isozymes at low concentrations and CYP3A4 isozymes at higher concentrations [284][285][286][287][288][289]. CYP2C and CYP3A4 are induced by carbamazepine, topiramate, and phenytoin, and inhibited valproate and other drugs [290].…”

A User’s Guide to Cannabinoid Therapies in Oncology

“…Absorption of both thc and cbd from the gastrointestinal tract is good, but both molecules undergo extensive first-pass metabolism. The bioavailability of orally administered thc and cbd is in the range of only 2%-20% 5,[17][18][19][20][21][22] . Table i summarizes the pharmacokinetic profiles of the various forms of cannabinoid therapies 5,[17][18][19][20][21][22] .…”

“…The bioavailability of smoked or vaporized thc is 10%-25% and depends on the duration of breath hold and depth of inhalation 5,[17][18][19][20][21][22] . Peak serum concentrations occur within 2-10 minutes.…”

Scientific Opinion on the risks for human health related to the presence of tetrahydrocannabinol (THC) in milk and other food of animal origin

“…Higher doses of CBD can potentiate the effects of lower doses of Δ 9 -THC by enhancing the level of CB 1 receptor expression in the hippocampus and hypothalamus (Russo and Guy, 2006;Aktories et al, 2009;Hazekamp and Grotenhermen, 2010;Ashton, 2001). On the other hand, several in vitro studies have shown that CBD is a powerful inhibitor of several human CYPs, including those belonging to the 2C and 3A families, which are responsible for the oxidative biotransformation of Δ 9 -THC (Stout and Cimino, 2014), and is able to reduce the formation of Δ 9 -THC metabolites when preincubated with liver human microsomes (Jaeger et al, 1996). Accordingly, as reflected by the plasma levels of Δ 9 -THC, 11-OH-THC, a partial inhibition of the hydroxylation of Δ 9 -THC to 11-OH-Δ 9 -THC was reported in male and female volunteers orally dosed with cannabis extract containing 10 mg Δ 9 -THC +5.4 mg CBD with respect to those receiving 10 mg Δ 9 -THC alone (Nadulski et al, 2005).…”

“…The pharmacokinetics and biotransformation pathways of CBD and CBN in humans and animals are similar to those of Δ 9 -THC (Agurell, 1986). Inhibitory effects on a wide array of human and rodent CYPs, as well as on human multidrug resistance-related protein 1 (MRP1) have been reported for both compounds (Stout and Cimino, 2014) with the potential for clinically relevant drug-drug interactions (Benowitz et al, 1980;Nadulski et al, 2005).…”