Predicting the potential for cannabinoids to precipitate pharmacokinetic drug interactions via reversible inhibition or inactivation of major cytochromes P450.

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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 (IC 50,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 IC 50,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 IC 50,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 (k inact/K I,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.

Keywords: CYP inhibition; Cannabinoid; Drug interactions; enzyme inactivation/mechanism-based inhibition; in vitro-in vivo prediction (IVIVE).

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