INVESTIGATION OF THE POTENTIAL DRUG-DRUG INTERACTIONS BETWEEN COMMONLY PRESCRIBED OPIOIDS AND CANNABINOIDS

Shelby Marie Coates Metra

doi:10.7273/000007067

Three commonly prescribed opioids to manage chronic pain are hydrocodone, hydromorphone, and morphine. Hydrocodone undergoes phase I metabolism by cytochrome P450 (CYP) 3A4 and 2D6 to form norhydrocodone and hydromorphone, respectively. Hydromorphone and morphine both undergo phase II metabolism by UDP-glucuronosyltransferase (UGT) 2B7 to form hydromorphone-3-glucuronide, morphine-3-glucuronide, and morphine-6-glucuronide, respectively. Studies have shown that up to 50% patients who are prescribed opioids to manage their chronic pain will co-use cannabis with their opioids. Previous in vitro studies have identified that major cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), and their metabolites 11-hydroxy-Δ9-tetrahydrocannabiol (11-OH-THC), 11-nor-9-carboxy- Δ9-tetrahydrocannabinol (11-COOH-THC), 7-hydroxy-cannabidiol (7-OH-CBD), and 7-carboxy cannabidiol (7-COOH-CBD), inhibit both CYP and UGT enzymes. To determine the inhibitory effect major cannabinoids and their metabolites have on opioid CYP and UGT mediated metabolism and drug interaction potential, in vitro and in vitro to in vivo extrapolation studies were performed. In vitro assays demonstrated that CBD competitively inhibited CYP3A4 mediated hydrocodone metabolism. THC, 11-OH-THC, CBD, and 7-OH-CBD were shown to competitively inhibit hydromorphone UGT2B7 mediated metabolism and that THC, 11-OH-THC, CBD, and 7-OH-CBD strongly inhibited UGT2B7 mediated morphine metabolism. Static mechanistic modeling utilizing the generated in vitro data indicated that major cannabinoids and their metabolites would cause a pharmacokinetic drug-drug interaction in vivo if THC or CBD were concomitantly used with either hydrocodone, hydromorphone, or morphine (AUCR > 1.25). The strongest inhibition was exhibited by CBD against all three enzymes. Further drug interaction predictions utilizing physiologically based pharmacokinetic (PBPK) modeling between CBD and morphine showed a modest increase in morphine exposure (morphine AUCR < 1.25), and the drug interaction between CBD and hydromorphone showed a clinically relevant increase in hydromorphone exposure (hydromorphone AUCR > 1.25). The clinically relevant increase in hydromorphone exposure and modest increase in morphine exposure are both clinically relevant as opioids have narrow therapeutic windows and exceeding the minimum toxic concentration will lead to adverse side effects. The findings presented in this dissertation indicate that major cannabinoids and their metabolites will inhibit both phase I and phase II enzymes involved in hydrocodone, hydromorphone, and morphine metabolism in vivo, potentially causing adverse drug events. Furthermore, genotype affects the severity of the potential drug-drug interaction between opioids and cannabinoids. These findings will help clinicians determine the safety of concomitantly using opioids with cannabis in the chronic pain population specifically and be used to determine the safety of using cannabis with other drugs that are also metabolized by CYP2D6, CYP3A4, and UGT2B7.

INVESTIGATION OF THE POTENTIAL DRUG-DRUG INTERACTIONS BETWEEN COMMONLY PRESCRIBED OPIOIDS AND CANNABINOIDS

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