RT Journal Article
SR Electronic
T1 <strong>Predicting the potential for cannabinoids to precipitate pharmacokinetic drug interactions via reversible inhibition or inactivation of major cytochromes P450</strong>
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2020-000073
DO 10.1124/dmd.120.000073
A1 Sumit Bansal
A1 Neha Maharao
A1 Mary F. Paine
A1 Jashvant D. Unadkat
YR 2020
UL http://dmd.aspetjournals.org/content/early/2020/06/25/dmd.120.000073.abstract
AB Cannabis is used for both recreational and medicinal purposes. The most abundant constituents are the cannabinoids - cannabidiol (CBD, non-psychoactive) and (−)-trans-Δ⁹-tetrahydrocannabinol (THC, psychoactive). Both have been reported to reversibly inhibit or inactivate cytochrome P450 (CYP) enzymes. However, the low aqueous solubility, microsomal protein binding, and non-specific binding to labware were not considered, potentially leading to an underestimation of CYP inhibition potency. Therefore, the binding-corrected reversible (IC50,u)and irreversible (KI,u) inhibition potency of each cannabinoid towards major CYPs were determined. The fraction unbound of CBD and THC in the incubation mixture was 0.12 {plus minus} 0.04 and 0.05 {plus minus} 0.02, respectively. The IC50,u for CBD towards CYPs 1A2, 2C9, 2C19, 2D6, and 3A was 0.45 {plus minus} 0.17, 0.17 {plus minus} 0.03, 0.30 {plus minus} 0.06, 0.95 {plus minus} 0.50, and 0.38 {plus minus} 0.11 µM, respectively; the IC50,u for THC was 0.06 {plus minus} 0.02, 0.012 {plus minus} 0.001, 0.57 {plus minus} 0.22, 1.28 {plus minus} 0.25, and 1.30 {plus minus} 0.34 µM, respectively. Only CBD showed time-dependent inactivation (TDI) of CYPs 1A2, 2C19, and CYP3A, with inactivation efficiencies (kinact/KI,u) of 0.70 {plus minus} 0.34, 0.11 {plus minus} 0.06, and 0.14 {plus minus} 0.04 min-1µM-1, respectively. A combined (reversible inhibition and TDI) mechanistic static model populated with these data predicted a moderate to strong pharmacokinetic interaction risk between orally administered CBD and drugs extensively metabolized by CYP1A2/2C9/2C19/2D6/3A and between orally administered THC and drugs extensively metabolized by CYP1A2/2C9/3A. These predictions will be extended to a dynamic model using physiologically-based pharmacokinetic modeling and simulation and verified with a well-designed clinical cannabinoid-drug interaction study.