Cannabinoid DMPK and DDIs: Getting into the Weeds | Dr. Jashvant Unadkat

The use of cannabis (aka marijuana) products for medicinal and non-medicinal purposes continues to increase globally. The cannabis constituent delta-9 tetrahydrocannabinol (THC) and its metabolite, 11-hydroxy-THC (11-OH-THC), produce the intoxicating (pharmacodynamics, PD) effect of cannabis. In contrast, the other major cannabinoid in cannabis, cannabidiol (CBD), is not intoxicating. THC is primarily cleared from the body by hepatic cytochrome P450 2C9 metabolism to its intoxicating metabolite 11-hydroxy-THC (1-2). THC is also metabolized in the human intestine (primarily by CYP3A and 2C9), and fetal liver (CYP3A7), but it is not metabolized in the human lung or placenta (3). In contrast, CBD is primarily cleared from the body by UGT (~80%) and CYP (~20%) metabolism (unpublished data). Both CBD and THC, are potent inhibitors of several CYP and UGT enzymes [4-6]. In vitro (human liver microsomes) and in vivo (in healthy participants) drug interaction (DI) studies have been conducted to predict the magnitude of these cannabinoids to precipitate DIs with CYP- and UGT-metabolized drugs. In addition, PBPK models of these cannabinoids have been developed (7-8, unpublished data) to predict their disposition in special populations (e.g. hepatically impaired, pediatric and pregnant women) and their PK/PD relationship (THC only). Findings from these studies will be presented and discussed. Supported by NIH grants U54 AT008909, P01 DA032507. 

1. Patilea-Vrana GI, Anoshchenko O, Unadkat JD. Hepatic Enzymes Relevant to the Disposition of (-)-?9-Tetrahydrocannabinol (THC) and Its Psychoactive Metabolite, 11-OH-THC. Drug Metab Dispos. 2019 Mar;47(3):249-256. doi: 10.1124/dmd.118.085548. Epub 2018 Dec 19. PMID: 30567877; PMCID: PMC6374540.
2. Patilea-Vrana GI, Unadkat JD. Quantifying hepatic enzyme kinetics of (-)-? 9-Tetrahydrocannabinol (THC) and its psychoactive metabolite, 11-OH-THC, through in vitro modeling. Drug Metabolism and Disposition. 2019 Jul 1;47(7):743-52.
3. Kumar AR, Patilea-Vrana GI, Anoshchenko O, Unadkat JD. Characterizing and Quantifying Extrahepatic Metabolism of (-)-?9-Tetrahydrocannabinol (THC) and Its Psychoactive Metabolite, (±)-11-Hydroxy-?9-THC (11-OH-THC). Drug Metab Dispos. 2022 Jun;50(6):734-740..
4. Bansal S, Maharao N, Paine MF, and Unadkat JD (2020) Predicting the Potential for Cannabinoids to Precipitate Pharmacokinetic Drug Interactions via Reversible Inhibition or Inactivation of Major Cytochromes P450. Drug Metab Dispos 48:1008-1017. 5. Bansal S, Paine MF, and Unadkat JD (2021) Can Cannabinoids Precipitate UGT-mediated Drug Interactions? The FASEB Journal 35:1-1.
6. Bansal S, Paine MF, and Unadkat JD (2022) Comprehensive predictions of cytochrome P450 (CYP)-mediated in vivo cannabinoid-drug interactions based on reversible and time-dependent CYP inhibition in human liver microsomes. Drug Metab Dispos 50:351-60.
7. Ladumor MK, Unadkat JD. Predicting Regional Respiratory Tissue and Systemic Concentrations of Orally Inhaled Drugs through a Novel PBPK Model. Drug Metabolism and Disposition. 2022;50(5):519-28.
8. Patilea-Vrana GI, Unadkat JD. Development and Verification of a Linked ?9-THC/11-OH-THC Physiologically Based Pharmacokinetic Model in Healthy, Nonpregnant Population and Extrapolation to Pregnant Women. Drug Metab Dispos. 2021 Jul;49(7):509-520.