Cannabis is used for both recreational and medicinal purposes. The most abundant constituents are the cannabinoids -cannabidiol (CBD, nonpsychoactive) and (2)-trans-D 9 -tetrahydrocannabinol (THC, psychoactive). Both have been reported to reversibly inhibit or inactivate cytochrome P450 (CYPs) enzymes. However, the low aqueous solubility, microsomal protein binding, and nonspecific binding to labware were not considered, potentially leading to an underestimation of CYPs inhibition potency. Therefore, the bindingcorrected reversible (IC 50,u ) and irreversible (K I,u ) inhibition potency of each cannabinoid toward major CYPs were determined. The fraction unbound of CBD and THC in the incubation mixture was 0.12 6 0.04 and 0.05 6 0.02, respectively. The IC 50,u for CBD toward CYP1A2, 2C9, 2C19, 2D6, and 3A was 0.45 6 0.17, 0.17 6 0.03, 0.30 6 0.06, 0.95 6 0.50, and 0.38 6 0.11 mM, respectively; the IC 50,u for THC was 0.06 6 0.02, 0.012 6 0.001, 0.57 6 0.22, 1.28 6 0.25, and 1.30 6 0.34 mM, respectively. Only CBD showed time-dependent inactivation (TDI) of CYP1A2, 2C19, and CYP3A, with inactivation efficiencies (k inact /K I,u ) of 0.70 6 0.34, 0.11 6 0.06, and 0.14 6 0.04 minutes 21 mM 21 , 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. SIGNIFICANCE STATEMENTThis study is the first to consider the impact of limited aqueous solubility, nonspecific binding to labware, or extensive binding to incubation protein shown by cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) on their true cytochrome P450 inhibitory potency. A combined mechanistic static model predicted a moderate to strong pharmacokinetic interaction risk between orally administered CBD and drugs extensively metabolized by CYP1A2, 2C9, 2C19, 2D6, or 3A and between orally administered THC and drugs extensively metabolized by CYP1A2, 2C9, or 3A.

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The COVID-19 pandemic has reached over 100 million worldwide. Due to the multi-targeted nature of the virus, it is clear that drugs providing anti-COVID-19 effects need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically angiotensin-converting enzyme (ACE), and Ca2+-mediated SARS-CoV-2 cellular entry and replication are noteworthy. A combination of ACE inhibitors and calcium channel blockers (CCBs), a critical line of therapy for pulmonary hypertension, has shown therapeutic relevance in COVID-19 when investigated independently. To that end, we conducted in silico modeling using BIOiSIM, an AI-integrated mechanistic modeling platform by utilizing known preclinical in vitro and in vivo datasets to accurately simulate systemic therapy disposition and site-of-action penetration of the CCBs and ACEi compounds to tissues implicated in COVID-19 pathogenesis.

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