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

Article Details

Citation

Stout SM, Cimino NM

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

Drug Metab Rev. 2014 Feb;46(1):86-95. doi: 10.3109/03602532.2013.849268. Epub 2013 Oct 25.

PubMed ID
24160757 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drugs
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
CannabidiolCytochrome P450 1A2ProteinHumans
Unknown
Inhibitor
Details
CannabidiolCytochrome P450 1B1ProteinHumans
Unknown
Inhibitor
Details
CannabidiolCytochrome P450 3A7ProteinHumans
Unknown
Inhibitor
Details
NabiximolsCytochrome P450 1A1ProteinHumans
Unknown
Inhibitor
Details
NabiximolsCytochrome P450 1A2ProteinHumans
Unknown
Inhibitor
Details
NabiximolsCytochrome P450 3A7ProteinHumans
Unknown
Inhibitor
Details
Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
CannabidiolCytochrome P450 2D6ProteinHumans
Unknown
Substrate
Details
CannabidiolCytochrome P450 3A5ProteinHumans
Unknown
Substrate
Inhibitor
Details
NabiximolsCytochrome P450 2C19ProteinHumans
Unknown
Substrate
Details
NabiximolsCytochrome P450 2C9ProteinHumans
No
Substrate
Details
NabiximolsCytochrome P450 2D6ProteinHumans
Unknown
Substrate
Details
NabiximolsCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
NabiximolsCytochrome P450 3A5ProteinHumans
Unknown
Substrate
Details