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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 9 -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 9 -tetrahydrocannabinol (11-OH-THC), 11-nor-9-carboxy-Δ 9 -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 i,u 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.

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 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), and major THC metabolites, 11-hydroxy-Δ 9 -tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ 9 -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 50 values were determined in human liver microsomes (HLM), human kidney microsomes (HKM), and rUGTs and utilized to estimate the nonspecific, binding-corrected K i (K i,u ) values and predict the area under the concentration-time curve ratio (AUCR). The estimated K i,u 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 i,u 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.

Background: Hypoxic ischemic encephalopathy remains a significant cause of developmental disability. 1,2 The standard of care for term infants is hypothermia, which has multifactorial effects. 3-5 Therapeutic hypothermia upregulates the cold-inducible protein RNA binding motif 3 (RBM3) that is highly expressed in developing and proliferative regions of the brain. 6,7 The neuroprotective effects of RBM3 in adults are mediated by its ability to promote the translation of mRNAs such as reticulon 3 (RTN3). 8 METHODS: Hypoxia ischemia or control procedure was conducted in Sprague Dawley rat pups on postnatal day 10 (PND10). Pups were immediately assigned to normothermia or hypothermia at the end of the hypoxia. In adulthood, cerebellum-dependent learning was tested using the conditioned eyeblink reflex. The volume of the cerebellum and the magnitude of cerebral injury were measured. A second study quantified RBM3 and RTN3 protein levels in the cerebellum and hippocampus collected during hypothermia., Results: Hypothermia reduced cerebral tissue loss and protected cerebellar volume. Hypothermia also improved learning of the conditioned eyeblink response. RBM3 and RTN3 protein expression were increased in the cerebellum and hippocampus of rat pups subjected to hypothermia on PND10., Conclusions: Hypothermia was neuroprotective in male and female pups and reversed subtle changes in the cerebellum after hypoxic ischemic., Impact: Hypoxic ischemic produced tissue loss and a learning deficit in the cerebellum. Hypothermia reversed both the tissue loss and learning deficit. Hypothermia increased cold-responsive protein expression in the cerebellum and hippocampus. Our results confirm cerebellar volume loss contralateral to the carotid artery ligation and injured cerebral hemisphere, suggesting crossed-cerebellar diaschisis in this model. Understanding the endogenous response to hypothermia might improve adjuvant interventions and expand the clinical utility of this intervention., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

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 IC 50,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 IC 50,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 IC 50,u values were observed in HLM. Inhibition (IC 50,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.

Introduction: 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., Area Covered: 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., Expert Opinion: Based upon the current literature, there is a strong potential for cannabis-induced DDI among major drug-metabolizing enzymes.

Loss-of-function mutations in the synaptic protein neurexin1α (NRXN1α) are associated with several neurodevelopmental disorders, including autism spectrum disorder (ASD), schizophrenia, and attention-deficit hyperactivity disorder (ADHD), and many of these disorders are defined by core deficits in social cognition. Mouse models of Nrxn1α deficiency are not amenable to studying aspects of social cognition because, in general, mice do not engage in complex social interactions such as social play or prosocial helping behaviors. Rats, on the contrary, engage in these complex, well-characterized social behaviors. Using the Nrxn1tm1Sage Sprague Dawley rat, we tested a range of cognitive and social behaviors in juveniles with haplo- or biallelic Nrxn1α mutation. We found a deficit in ultrasonic vocalizations (USVs) of male and female neonatal rats with Nrxn1α deficiency. A male-specific deficit in social play was observed in Nrxn1α-deficient juveniles, although sociability and social discrimination were unaltered. Nurturing behavior induced by exposure to pups was enhanced in male and female juveniles with biallelic Nrxn1α mutation. Performance in tasks of prosocial helping behavior and food retrieval indicated severe deficits in learning and cognition in juveniles with biallelic Nrxn1α mutation, and a less severe deficit in haploinsufficient rats, although Pavlovian learning was altered only in haploinsufficient males. We also observed a male-specific increase in mobility and object investigation in juveniles with complete Nrxn1α deficiency. Together, these observations more fully characterize the Nrxn1tm1Sage Sprague Dawley rat as a model for Nrxn1α-related neurodevelopmental disorders, and support a rationale for the juvenile rat as a more appropriate model for disorders that involve core deficits in complex social behaviors. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The UDP-glucuronosyltransferase (UGT) family of enzymes play a central role in the metabolism and detoxification of a wide range of endogenous and exogenous compounds. UGTs exhibit a high degree of structural similarity and display overlapping substrate specificity, often making estimations of potential drug-drug interactions difficult to fully elucidate. One such interaction yet to be examined may be occurring between UGTs and cannabinoids, as the legalization of recreational and medicinal cannabis and subsequent co-usage of cannabis and therapeutic drugs increases in the United States and internationally. In the present study, the inhibition potential of the major cannabinoids Δ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), as well as their major metabolites, was determined in microsomes isolated from HEK293 cells overexpressing individual recombinant UGTs and in microsomes from human liver and kidney specimens. The highest inhibition was seen by CBD against the glucuronidation activity of UGTs 1A9, 2B4, 1A6, and 2B7, with binding-corrected IC 50 values of 0.12 ± 0.020 µM, 0.22 ± 0.045 µM, 0.40 ± 0.10 µM, and 0.82 ± 0.15 µM, respectively. Strong inhibition of UGT1A9 was also demonstrated by THC and CBN, with binding-corrected IC 50 values of 0.45 ± 0.12 μM and 0.51 ± 0.063 μM, respectively. Strong inhibition of UGT2B7 was also observed for THC and CBN; no or weak inhibition was observed with cannabinoid metabolites. This inhibition of UGT activity suggests that in addition to playing an important role in drug-drug interactions, cannabinoid exposure may have important implications in patients with impaired hepatic or kidney function. SIGNIFICANCE STATEMENT: Major cannabinoids found in the plasma of cannabis users inhibit several UDP-glucuronosyltransferase (UGT) enzymes, including UGT1A6, UGT1A9, UGT2B4, and UGT2B7. This study is the first to show the potential of cannabinoids and their metabolites to inhibit all the major kidney UGTs as well as the two most abundant UGTs present in liver. This study suggests that as all three major kidney UGTs are inhibited by cannabinoids, greater drug-drug interaction effects might be observed from co-use of cannabinods and therapeutics that are cleared renally., (Copyright © 2021 by The Author(s).)

Working with a combination of ProMOL (a plugin for PyMOL that searches a library of enzymatic motifs for local structural homologs), BLAST and Pfam (servers that identify global sequence homologs), and Dali (a server that identifies global structural homologs), we have begun the process of assigning functional annotations to the approximately 3,500 structures in the Protein Data Bank that are currently classified as having "unknown function". Using a limited template library of 388 motifs, over 500 promising in silico matches have been identified by ProMOL, among which 65 exceptionally good matches have been identified. The characteristics of the exceptionally good matches are discussed.