Opioids including morphine are mu‐opioid receptor (MOR) agonists that suppress excitatory neurotransmitter release, hyperpolarize neuronal cells, and decrease overall excitability, resulting in the ...desired analgesic effect. As a result of their over‐prescription, the still‐growing opioid epidemic has devastated many communities, with many individuals often using them in combination with other drugs including cannabis. Morphine is primarily metabolized by the phase II enzyme UDP‐glucuronosyltransferase (UGT) 2B7 to an inactive metabolite, morphine‐3‐glucuronide (M3G), and an active metabolite, morphine‐6‐glucuronide (M6G), both of which are extensively excreted into the urine. Previous studies in our lab have shown that major cannabis constituents including Δ9‐tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) inhibit several major UGT enzymes. To examine whether cannabinoids or their major metabolites inhibit morphine glucuronidation by UGT2B7, screening assays were performed in pooled human liver microsomes (HLM) with the major cannabinoids and THC metabolites, 11‐hydroxy‐Δ9‐tetrahydrocannabinol (11‐OH‐THC), 11‐nor‐9‐carboxy‐Δ9‐tetrahydrocannabinol (11‐COOH‐THC), and 11‐nor‐Δ9‐tetrahydrocannabinol‐carboxylic acid glucuronide (THC‐COO‐Gluc). IC50 values were then determined for those cannabinoids that exhibited at least 50% inhibition at 100 µM final concentration. THC, 11‐OH‐THC, THC‐COO‐Gluc, and CBD all exhibited greater than 50% inhibition of both M3G and M6G formation at either 10 or 100 µM. The IC50 values for THC, 11‐OH‐THC, THC‐COO‐Gluc, and CBD against M3G formation were determined to be 27 ± 9.97 µM, 5.97 ± 2.31 µM, 15.58 ± 12.28 µM, and 15.66 ± 19.98 µM, respectively. The IC50 values for THC, 11‐OH‐THC, THC‐COO‐Gluc, and CBD against M6G formation were 14.49 ± 4.03 µM, 6.26 ± 0.76 µM, 13.22 ± 5.28 µM, and 8.12 ± 9.64 µM, respectively. To confirm results from these inhibition screenings, M3G and M6G formation were further examined using microsomal fractions from HEK293 cells overexpressing recombinant UGT2B7. THC, 11‐OH‐THC, THC‐COO‐Gluc, and CBD all exhibited >50% inhibition of both M3G and M6G formation at either 10 or 100 µM in the recombinant enzyme system. These data suggest that several cannabinoids and their metabolites inhibit morphine metabolism, and that the co‐use of these agents may lead to adverse drug events in humans.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
With the rapid increase in cancer survival because of improved diagnosis and therapy in the past decades, cancer treatment–related cardiotoxicity is becoming an urgent healthcare concern. The ...anthracycline doxorubicin (DOX), one of the most effective chemotherapeutic agents to date, causes cardiomyopathy by inducing cardiomyocyte apoptosis. We demonstrated previously that overexpression of the cyclin-dependent kinase (CDK) inhibitor p21 promotes resistance against DOX-induced cardiomyocyte apoptosis. Here we show that DOX exposure provokes cardiac CDK2 activation and cardiomyocyte cell cycle S phase reentry, resulting in enhanced cellular sensitivity to DOX. Genetic or pharmacological inhibition of CDK2 markedly suppressed DOX-induced cardiomyocyte apoptosis. Conversely, CDK2 overexpression augmented DOX-induced apoptosis. We also found that DOX-induced CDK2 activation in the mouse heart is associated with up-regulation of the pro-apoptotic BCL2 family member BCL2-like 11 (Bim), a BH3-only protein essential for triggering Bax/Bak-dependent mitochondrial outer membrane permeabilization. Further experiments revealed that DOX induces cardiomyocyte apoptosis through CDK2-dependent expression of Bim. Inhibition of CDK2 with roscovitine robustly repressed DOX-induced mitochondrial depolarization. In a cardiotoxicity model of chronic DOX exposure (5 mg/kg weekly for 4 weeks), roscovitine administration significantly attenuated DOX-induced contractile dysfunction and ventricular remodeling. These findings identify CDK2 as a key determinant of DOX-induced cardiotoxicity. CDK2 activation is necessary for DOX-induced Bim expression and mitochondrial damage. Our results suggest that pharmacological inhibition of CDK2 may be a cardioprotective strategy for preventing anthracycline-induced heart damage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Opioids are commonly prescribed for the treatment of chronic pain. Approximately 50% of adults who are prescribed opioids for pain co-use cannabis with their opioid treatment. Morphine is primarily ...metabolized by UDP-glucuronosyltransferase (UGT) 2B7 to an inactive metabolite, morphine-3-glucuronide (M3G), and an active metabolite, morphine-6-glucuronide (M6G). Previous studies have shown that major cannabis constituents including Δ
-tetrahydrocannabinol (THC) and cannabidiol (CBD) inhibit major UGT enzymes. To examine whether cannabinoids or their major metabolites inhibit morphine glucuronidation by UGT2B7, in vitro assays and mechanistic static modeling were performed with these cannabinoids and their major metabolites including 11-hydroxy-Δ
-tetrahydrocannabinol (11-OH-THC), 11-nor-9-carboxy-Δ
-tetrahydrocannabinol (11-COOH-THC), 7-hydroxy-cannabidiol (7-OH-CBD), and 7-carboxy-cannabidiol (7-COOH-CBD). In vitro assays with rUGT-overexpressing microsomes and human liver microsomes showed that THC and CBD and their metabolites inhibited UGT2B7-mediated morphine metabolism, with CBD and THC exhibiting the most potent K
values (0.16 µM and 0.37 µM, respectively). Only 7-COOH-CBD exhibited no inhibitory activity against UGT2B7-mediated morphine metabolism. Static mechanistic modeling predicted an in vivo drug-drug interaction between morphine and THC after inhaled cannabis, and between THC, CBD, and 7-OH-CBD after oral consumption of cannabis. These data suggest that the co-use of these agents may lead to adverse drug events in humans.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Benzodiazepines (BZDs) such as oxazepam are commonly prescribed depressant drugs known for their anxiolytic, hypnotic, muscle relaxant, and anticonvulsant effects and are frequently used in ...conjunction with other illicit drugs including cannabis. Oxazepam is metabolized in an enantiomeric-specific manner by glucuronidation, with S-oxazepam metabolized primarily by UGT2B15 and R-oxazepam glucuronidation mediated by both UGT 1A9 and 2B7. The goal of the present study was to evaluate the potential inhibitory effects of major cannabinoids, Δ
-tetrahydrocannabinol (THC) and cannabidiol (CBD), and major THC metabolites, 11-hydroxy-Δ
-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ
-tetrahydrocannabinol (11-COOH-THC), on the UGT-mediated metabolism of R- and S-oxazepam. The cannabinoids and metabolites were screened as inhibitors of R- and S-oxazepam glucuronidation in microsomes isolated from HEK293 cells overexpressing individual UGT enzymes (rUGTs). The IC
values were determined in human liver microsomes (HLM), human kidney microsomes (HKM), and rUGTs and utilized to estimate the nonspecific, binding-corrected K
(K
) values and predict the area under the concentration-time curve ratio (AUCR). The estimated K
values observed in HLM for S- and R-oxazepam glucuronidation by CBD, 11-OH-THC, and THC were in the micromolar range (0.82 to 3.7 µM), with the K
values observed for R-oxazepam glucuronidation approximately 2- to 5-fold lower as compared to those observed for S-oxazepam glucuronidation. The mechanistic static modeling predicted a potential clinically significant interaction between oral THC and CBD with oxazepam, with the AUCR values ranging from 1.25 to 3.45. These data suggest a pharmacokinetic drug-drug interaction when major cannabinoids like CBD or THC and oxazepam are concurrently administered.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Awareness of drug interactions involving opioids is critical for patient treatment as they are common therapeutics used in numerous care settings, including both chronic and disease-related pain. Not ...only do opioids have narrow therapeutic indexes and are extensively used, but they have the potential to cause severe toxicity. Opioids are the classical pain treatment for patients who suffer from moderate to severe pain. More importantly, opioids are often prescribed in combination with multiple other drugs, especially in patient populations who typically are prescribed a large drug regimen. This review focuses on the current knowledge of common opioid drug-drug interactions (DDIs), focusing specifically on hydrocodone, oxycodone, and morphine DDIs. The DDIs covered in this review include pharmacokinetic DDI arising from enzyme inhibition or induction, primarily due to inhibition of cytochrome p450 enzymes (CYPs). However, opioids such as morphine are metabolized by uridine-5'-diphosphoglucuronosyltransferases (UGTs), principally UGT2B7, and glucuronidation is another important pathway for opioid-drug interactions. This review also covers several pharmacodynamic DDI studies as well as the basics of CYP and UGT metabolism, including detailed opioid metabolism and the potential involvement of metabolizing enzyme gene variation in DDI. Based upon the current literature, further studies are needed to fully investigate and describe the DDI potential with opioids in pain and related disease settings to improve clinical outcomes for patients. SIGNIFICANCE STATEMENT: A review of the literature focusing on drug-drug interactions involving opioids is important because they can be toxic and potentially lethal, occurring through pharmacodynamic interactions as well as pharmacokinetic interactions occurring through inhibition or induction of drug metabolism.
Cannabis-based products have experienced notable increases in co-usage alongside tobacco products. Several cannabinoids exhibit inhibition of a number of cytochrome P450 (CYP) and UDP ...glucuronosyltransferase (UGT) enzymes, but few studies have examined their inhibition of enzymes involved in nicotine metabolism. The goal of the present study was to examine potential drug–drug interactions occurring in the nicotine metabolism pathway perpetrated by cannabidiol (CBD) and its active metabolite, 7-hydroxy-CBD (7-OH-CBD). The inhibitory effects of CBD and 7-OH-CBD were tested in microsomes from HEK293 cells overexpressing individual metabolizing enzymes and from human liver tissue. Assays with overexpressing microsomes demonstrated that CBD and 7-OH-CBD inhibited CYP-mediated nicotine metabolism. Binding-corrected IC50,u values for CBD inhibition of nicotine metabolism to cotinine and nornicotine, and cotinine metabolism to trans-3′-hydroxycotinine (3HC), were 0.27 ± 0.060, 0.23 ± 0.14, and 0.21 ± 0.14 μM, respectively, for CYP2A6; and 0.26 ± 0.17 and 0.029 ± 0.0050 μM for cotinine and nornicotine formation, respectively, for CYP2B6. 7-OH-CBD IC50,u values were 0.45 ± 0.18, 0.16 ± 0.08, and 0.78 ± 0.23 μM for cotinine, nornicotine, and 3HC formation, respectively, for CYP2A6, and 1.2 ± 0.44 and 0.11 ± 0.030 μM for cotinine and nornicotine formation, respectively, for CYP2B6. Similar IC50,u values were observed in HLM. Inhibition (IC50,u = 0.37 ± 0.06 μM) of 3HC to 3HC-glucuronide formation by UGT1A9 was demonstrated by CBD. Significant inhibition of nicotine metabolism pathways by CBD and 7-OH-CBD suggests that cannabinoids may inhibit nicotine metabolism, potentially impacting tobacco addiction and cessation.
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IJS, KILJ, NUK, PNG, UL, UM
Cannabis is an increasingly popular recreational and medicinal drug in the USA. While cannabis is still a Schedule 1 drug federally, many states have lifted the ban on its use. With its increased ...usage, there is an increased possibility for potential drug-drug interactions (DDI) that may occur with concomitant use of cannabis and pharmaceuticals.
This review focuses on the current knowledge of cannabis induced DDI, with a focus on pharmacokinetic DDI arising from enzyme inhibition or induction. Phase I and phase II drug metabolizing enzymes, specifically cytochrome P450s, carboxylesterases, and uridine-5'-diphosphoglucuronosyltransferases, have historically been the focus of research in this field, with much of the current knowledge of the potential for cannabis to induce DDI within these families of enzymes coming from in vitro enzyme inhibition studies. Together with a limited number of in vivo clinical studies and in silico investigations, current research suggests that cannabis exhibits the potential to induce DDI under certain circumstances.
Based upon the current literature, there is a strong potential for cannabis-induced DDI among major drug-metabolizing enzymes.
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