morphine-6-glucuronide (M6G) / PAION, Humanwell Healthcare - LARVOL DELTA

Pharmacokinetics and Pharmacodynamics of Intranasal Diacetylmorphine in Heroin-Assisted Treatment for Severe Opioid Use Disorder. (PubMed, CNS Drugs) - "IN DAM has a good safety profile and should be considered as an effective alternative for patients in HAT, offering rapid onset of effects without significant side effects. Optimization of intranasal delivery may further improve absorption and clinical utility."

Journal • PK/PD data • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Psychiatry • Substance Abuse

Scoping Review of Paediatric Population Pharmacokinetic Models of Morphine. (PubMed, Clin Pharmacokinet) - "Several population pharmacokinetic models of morphine and its metabolites in paediatrics have been published across diverse patient groups. Bodyweight and age-related covariates emerged as the most common factors affecting clearance and distribution; other covariates, including mechanical ventilation, therapeutic cooling, and genetic variation, also impacted morphine pharmacokinetics. Further research should focus on validating the predictive accuracy of paediatric morphine models in different patient populations and the combined effect of covariates, such as those related to critical illness and genetic variation, on morphine pharmacokinetics."

Journal • PK/PD data • Review • Pediatrics • SLC22A1

Pharmacokinetics and thermal anti-nociceptive effects of oral morphine in horses. (PubMed, Front Vet Sci) - "The analgesic effects of morphine have, at least in part, been attributed to the morphine-6-glucuronide (M6G) metabolite. Morphine was well tolerated following oral administration with less excitation and minimal effects on gastrointestinal borborygmi scores compared to IV administration. Results of the current study warrant further investigation of the anti-nociceptive effects of oral morphine administration to horses."

Journal • PK/PD data • Gastrointestinal Disorder • Pain

The role of drug efflux and uptake transporters in the plasma pharmacokinetics and tissue disposition of morphine and its main metabolites. (PubMed, Toxicol Appl Pharmacol) - "Morphine is a widely used opioid for the treatment of pain. The ablation of mOatp1a/1b increases plasma exposure and decreases the liver and small intestinal disposition of M3G and M6G. Since the contribution of human OATP1B1/1B3 to M6G liver uptake was quite modest, the risks of undesirable drug interactions or interindividual variation related to OATP activity are likely negligible."

Journal • PK/PD data • Pain • ABCB1 • ABCG2 • SLCO2B1

Pharmacokinetic and neuroimmune pharmacogenetic impacts on slow-release morphine cancer pain control and adverse effects. (PubMed, Pharmacogenomics J) - "The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02-0.63)) and IL6R rs8192284 carrier (0.55 (0.34-0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2-9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients."

Adverse events • Biomarker • Journal • PK/PD data • Cognitive Disorders • Oncology • Pain • BDNF • IL2 • IL6R • TLR2

Non-linear blood-brain barrier transport and dosing strategies influence receptor occupancy ratios of morphine and its metabolites in pain matrix. (PubMed, Br J Pharmacol) - "Non-linear BBB transport of morphine affects the μ-receptor occupancy ratios of morphine with its metabolites, depending on dose and route of administration, and CNS location. These predictions need validation in animal or clinical experiments, to understand the clinical implications."

Journal • Pain

Incidence of drug-related adverse events related to the use of high-alert drugs: A systematic review of randomized controlled trials. (PubMed, Explor Res Clin Soc Pharm) - "The most reported drug classes in the articles included that were related to incidence of drug-related adverse events in use of high-alert medications: morphine, M6G-glucuronide, haloperidol, promethazine, ivabradine, digoxin, warfarin, ximelagatran, cyclophosphamide, cyclosporine, and ATG. The formulate protocols for the use of these medications, with importance placed on evaluating, among the classes, the medication that causes the least harm."

Adverse events • Journal • Review • Cardiovascular • Hematological Disorders • Infectious Disease • Thrombosis • Venous Thromboembolism

PBPK-PD model for predicting morphine pharmacokinetics, CNS effects and naloxone antagonism in humans. (PubMed, Acta Pharmacol Sin) - "Pharmacokinetics and antagonistic effects of naloxone on CNS effects were also successfully predicted using the developed PBPK-PD model. In conclusion, the pharmacokinetics and pharmacodynamics of morphine and M6G, antagonistic effects of naloxone against morphine-induced CNS effects may be successfully predicted using the developed PBPK-PD model based on the parameters derived from in vitro, in silico, or animal studies."

Journal • PK/PD data • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Ophthalmology • Psychiatry

Development and validation of an LC-MS/MS method for quantifying diamorphine and its major metabolites 6-monoacetylmorphine, morphine, morphine-3-glucuronide, and morphine-6-glucuronide in human plasma. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "Lastly, we applied the method to assess the plasma concentrations of an opioid-dependent patient after the intranasal administration of diamorphine in a clinical study. In summary, we have successfully developed a rapid, highly reliable, and straightforward bioanalytical method for quantifying diamorphine and its metabolites in low amounts of clinical plasma samples."

Journal • Addiction (Opioid and Alcohol) • Pain

Cannabinoid-Induced Inhibition of Morphine Glucuronidation and the Potential for In Vivo Drug-Drug Interactions. (PubMed, Pharmaceutics) - "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). 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."

Journal • Preclinical • Pain

Dissecting the innate immune recognition of morphine and its metabolites by TLR4/MD2: an in silico simulation study. (PubMed, Phys Chem Chem Phys) - "A toll-like receptor 4/myeloid differentiation factor 2 complex (TLR4/MD2) has been identified as a non-classical opioid receptor capable of recognizing morphine isomers and activating microglia in a non-enantioselective manner. These results indicate that the pivotal interactions at the dimerization interface between MD2 and TLR4* in M6G-bound (TLR4/MD2) were considerably weaker than those in M3G-bound (TLR4/MD2), which partially explains why M6G fails to activate TLR4 signaling. The discoveries from this study will offer valuable insights for the advancement of next-generation TLR4 small molecule modulators based on opioids."

Journal • TLR4

Influence of Intravenous S-Ketamine on the Pharmacokinetics of Oral Morphine in Healthy Volunteers. (PubMed, Anesth Analg) - "Intravenous S-ketamine inhibited the metabolism of oral morphine and delayed its absorption, resulting in a net reduction in the exposure to morphine during the first 1.5 hours. Intravenous S-ketamine may delay the absorption and impair the efficacy of orally administered analgesics and other drugs."

Clinical • Journal • PK/PD data • Pain

Exploring the molecular basis of mutational spectra generated by SN1 alkylating agents (ACS-Fall 2023) - "The present work utilizes this conceptual framework to investigate the molecular origins of the mutational spectra induced by SN1 DNA-methylating agents, including environmental carcinogen N-nitrosodimethylamine (NDMA) and chemotherapeutics temozolomide (TMZ), streptozotocin (STZ) and N-nitroso-N-methylurea (MNU). These mutational spectra are also very similar to human COSMIC mutational signature SBS11, commonly associated with alkylation damage. Studies with mice deficient for MGMT – the key repair protein for m6G suggest that the dominant factor in shaping the mutational spectra of SN1 alkylators is the sequence-specific lesion formation."

Brain Cancer • Genetic Disorders • Oncology • Solid Tumor

Plasma morphine and morphine-6-glucuronide during chronic morphine therapy for cancer pain: plasma profiles, steady-state concentrations and the consequences of renal failure: erratum. (PubMed, Pain) - No abstract available

Journal • Oncology • Pain • Renal Disease

Heroin and its metabolites: relevance to heroin use disorder. (PubMed, Transl Psychiatry) - "In contrast to these former views, we will argue for a more complex interplay among heroin and its active metabolites: 6-MAM, morphine, and morphine-6-glucuronide (M6G)...We will first review the literature concerning the pharmacokinetics and pharmacodynamics of heroin and its metabolites, then examine their neural and behavioral effects, and finally discuss the possible implications of these data for a better understanding of opioid reward and heroin addiction. By so doing we hope to highlight research topics to be investigated by future clinical and pre-clinical studies."

Journal • Review • Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry • Substance Abuse

Molecular origins of mutational spectra produced by the environmental carcinogen N-nitrosodimethylamine and S1 chemotherapeutic agents. (PubMed, NAR Cancer) - "Commonly associated with alkylation damage, SBS11 appears in cancers treated with the DNA alkylator temozolomide (TMZ). MGMT-deficient mice displayed a strikingly enhanced mutant frequency, but identical HRMS, indicating that the mutational properties of these alkylators is likely owed to sequence-specific DNA binding. In sum, the HRMS of m6G-forming agents constitute an early-onset biomarker of exposure to DNA methylating carcinogens and drugs."

Journal • Oncology

Concentrations, pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites following oral administration to horses. (PubMed, J Vet Pharmacol Ther) - "In this study, we hypothesized that oral administration would lead to comparable concentrations of morphine and its presumed active metabolite, morphine 6-glucuronide (M6G) without the adverse effects associated with i.v. administration. Behavioral and physiologic changes were noted in all groups but were less prominent with oral compared with i.v. administration. Results of the current study are encouraging for further study, specifically anti-nociceptive effects of morphine following oral administration."

Journal • PK/PD data • Gastrointestinal Disorder

Morphine in donkeys: antinociceptive effect and preliminary pharmacokinetics. (PubMed, Equine Vet J) - "The HDM treatment provided mechanical antinociception in donkeys with no significant adverse effects."

Journal • PK/PD data • Gastrointestinal Disorder

Pharmacological data science perspective on fatal incidents of morphine treatment. (PubMed, Pharmacol Ther) - "Morphine has pharmacological properties that make it particularly difficult to assess the causality of morphine administration with a patient's death, such as its slow transfer between plasma and central nervous sites of action and the existence of the active metabolite morphine-6-glucuronide with opioid agonistic effects, Furthermore, there is no well-defined toxic dose or plasma/blood concentration for morphine. A medicolegal case is presented in which the causality of morphine administration with death was in dispute and pharmacokinetic modeling was applied to infer the administered dose. The results of this analytical review suggest that (i) inference from postmortem blood concentrations to the morphine dose administered has low validity and (ii) causality between a patient's death and the morphine dose administered remains a highly context-dependent and collaborative assessment among experts from different medical specialties."

Journal • Review • Addiction (Opioid and Alcohol) • Pain

Opioid MOP receptor agonists in late-stage development for the treatment of postoperative pain. (PubMed, Expert Opin Pharmacother) - ": Oliceridine appears to be an effective and potentially safer μ opioid receptor agonist...Cebranopadol is an agonist at multiple opioid receptors, of which μ opioid and nociceptin/orphanin FQ peptide (NOP) receptor are most significant...Lastly, morphine-6-glucuronide is an active metabolite of morphine with a slower onset than its parent compound. It has failed to demonstrate appreciable benefit in the context of postoperative analgesia."

Journal • CNS Disorders • Depression • Neuralgia • Pain • Psychiatry

Characterization of the pharmacokinetics, behavioral effects and effects on thermal nociception of morphine 6-glucuronide and morphine 3-glucuronide in horses. (PubMed, Vet Anaesth Analg) - "Results of this study provide additional information regarding the use of morphine in horses. Less locomotor excitation and gastrointestinal adverse effects, compared with morphine, coupled with favorable effects on thermal nociception are encouraging for further study of the pharmacodynamics of both M6G and M3G in horses."

Journal • PK/PD data • Gastrointestinal Disorder

Design and synthesis of tools to assess the impact of 6-OMe guanosine on the stability of U2 snRNA under conditions of oxidative stress | Poster Board #2227 (ACS-Fall 2022) - "The aim of this research is to determine how the naturally occurring lesion O6-methylguanosine (m6G) in human U2 snRNA impacts its structure and function under conditions of oxidative stress. Specifically, an efficient synthetic method has been developed for a 5′-H-phosphonate-6-O-methyl-guanosine monomer, which can be incorporated into RNA oligonucleotides via novel reverse automated oligonucleotide synthesis. This substrate will facilitate the development of important tools for the further investigation of the impact of oxidative damage on RNA."

Alzheimer's Disease • CNS Disorders • Movement Disorders • Parkinson's Disease

Investigating the role of naturally occurring modifications in U2 snRNA under oxidative stress | Poster Board #2703 (ACS-Fall 2022) - "In humans, this oligomer contains methylated guanosine (m6G), 2'-O-methylated sugars, and pseudouridine...Findings of this research will provide tools for the study of oxidative damage to RNA and key roles of naturally occurring mutations in the structural stability of the spliceosomal complex under oxidative stress. It will further shed light on the underlying mechanisms behind the contributions of RNA oxidative damage to degenerative diseases."

Preliminary study of the pharmacokinetics, tissue distribution, and behavioral and select physiological effects of morphine 6-glucuronide (M6G) following intravenous administration to horses. (PubMed, Can J Vet Res) - "Following administration, M6G was detected in the kidney, liver, CSF, and regions of the brain. Results of this study encourage further investigation of M6G in order to assess its clinical feasibility as an analgesic in horses."

Journal • PK/PD data • Anesthesia • Ataxia • Movement Disorders • Pain

Simultaneous detection of a panel of nine sedatives and metabolites in plasma from critically ill pediatric patients via UPLC-MS/MS. (PubMed, J Pharm Biomed Anal) - "The goal of this project was to develop a sensitive and selective assay for the simultaneous quantification of a panel of sedatives comprised of midazolam (MDZ), alpha hydroxymidazolam (1- OH MDZ), dexmedetomidine (DEX), morphine (MOR), morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), fentanyl (FEN), norfentanyl (NF), and hydromorphone (HM) in small volume pediatric plasma samples. Initial testing of samples from pediatric patients demonstrates adequacy of assay to measure sedatives and metabolites at clinical concentrations confidently in low volumes of plasma. This novel highly-sensitive and specific method to measure a total of nine different analytes (five sedatives, four metabolites) simultaneously enables comprehensive analysis of a panel of sedatives in small volumes such as in pediatric ICU patients."

Journal • CNS Disorders • Critical care • Pediatrics