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British Journal of Clinical Pharmacology Jul 1999To measure morphine and morphine-6-glucuronide in the plasma and cerebrospinal fluid of children following a single intravenous dose of morphine. (Clinical Trial)
Clinical Trial
AIMS
To measure morphine and morphine-6-glucuronide in the plasma and cerebrospinal fluid of children following a single intravenous dose of morphine.
METHODS
Twenty-nine paired samples of cerebrospinal fluid and plasma were collected from children with leukaemia undergoing therapeutic lumbar puncture. An intravenous dose of morphine was administered at selected intervals before the procedure. Concentrations of morphine and morphine-6-glucuronide (M6G) were measured in each sample. Morphine was measured using a specific radioimmunoassay (r.i.a.) and M6G was measured using a novel enzyme-linked immunosorbent assay (ELISA).
RESULTS
The ELISA for measuring M6G was highly sensitive. The intra-and interassay variations were less than 15%. Using a two-compartment model for plasma morphine, the area under the curve to infinity (AUC, 7143 ng ml-1 min), volume of distribution (3.6 l kg-1 ) and elimination half-life (88 min) were comparable with those reported in adults. Clearance (35 ml min-1 ) was higher than that in adults. Morphine-6-glucuronide was readily synthesized by the children in this study. The elimination half-life (321 min) and AUC (35507 ng ml-1 min) of plasma M6G were much greater than those of morphine.
CONCLUSIONS
Extensive metabolism of morphine to M6G in children with cancer has been demonstrated. These data provide further evidence to support the importance of M6G accumulation after multiple doses. There was no evidence that morphine passed more easily into the CSF of children than adults.
Topics: Area Under Curve; Child; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant; Male; Morphine; Morphine Derivatives
PubMed: 10383558
DOI: 10.1046/j.1365-2125.1999.00948.x -
ACS Chemical Neuroscience Aug 2019Heroin rapidly enters the CNS but is quickly metabolized into 6-monoacetylmorphine (6-MAM) and then morphine. Although morphine is often thought to mediate heroin's...
Heroin rapidly enters the CNS but is quickly metabolized into 6-monoacetylmorphine (6-MAM) and then morphine. Although morphine is often thought to mediate heroin's neural effects, pharmacokinetic data question this view. To further understand the effects of heroin and its metabolites, oxygen sensors were used to examine changes in nucleus accumbens (NAc) oxygen levels. Heroin, 6-MAM, and morphine were all administered intravenously at two human-relevant doses (0.25 μmol/kg and 0.98 μmol/kg) in freely moving rats. Intravenous heroin induced a biphasic change in NAc oxygen, with a decrease resulting from respiratory depression and an increase resulting from cerebral vasodilation. 6-MAM caused similar but more rapid and slightly weaker effects than heroin. The stronger response to heroin can be primarily attributed to heroin's permeability and metabolism resulting in more 6-MAM in the brain. Morphine only induced weak increases in NAc oxygen. Therefore, it appears that 6-MAM is the major contributor to acute neural effects induced by iv heroin.
Topics: Analgesics, Opioid; Animals; Heroin; Male; Morphine; Morphine Derivatives; Nucleus Accumbens; Oxygen; Rats; Rats, Long-Evans
PubMed: 31268284
DOI: 10.1021/acschemneuro.9b00305 -
Fundamental & Clinical Pharmacology Aug 2011Although intravenous morphine titration (IMT) is widely used to control moderate to severe postoperative pain, the relationships between plasma concentrations of... (Clinical Trial)
Clinical Trial
Relationships between plasma concentrations of morphine, morphine-3-glucuronide, morphine-6-glucuronide, and intravenous morphine titration outcomes in the postoperative period.
Although intravenous morphine titration (IMT) is widely used to control moderate to severe postoperative pain, the relationships between plasma concentrations of morphine and its metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), and IMT outcomes in the postanesthesia care unit (PACU) have not been yet investigated. IMT was administrated as a bolus of 2 or 3 mg every 5 min. Titration was interrupted in case of pain relief (visual analog score ≤30), adverse events, sedation, or failure of morphine titration. Blood samples were collected at the end of morphine titration to determine plasma concentration of morphine and its two metabolites. Data from 214 patients were analyzed; 143 (67%) of the patients achieved complete pain relief, 39 (18%) experienced adverse events, and 32 (15%) failure of morphine titration. At the end of titration, there were no significant differences in morphine, M6G, M3G concentrations between sedated and nonsedated patients (32 vs. 42 ng/mL (P = 0.07), 38 vs. 45 ng/mL (P = 0.51), 300 vs. 342 ng/mL (P = 0.29), respectively), or patients with or without adverse events (40 vs. 41 ng/mL (P = 0.95), 37 vs. 46 ng/mL (P = 0.51), 287 vs. 340 ng/mL (P = 0.72), respectively). Our study demonstrated a lack of relationship between plasma concentrations or ratios of morphine, M3G, and M6G, with IMT outcomes in PACU. This result suggests that the kinetics of morphine and its metabolites have limited value for explaining clinical effects of morphine in this clinical setting.
Topics: Age Factors; Aged; Female; Humans; Injections, Intravenous; Male; Middle Aged; Morphine; Morphine Derivatives; Obesity; Pain Measurement; Pain, Postoperative; Postoperative Care; Sex Characteristics; Treatment Failure; Treatment Outcome
PubMed: 20825489
DOI: 10.1111/j.1472-8206.2010.00867.x -
British Journal of Clinical Pharmacology Sep 1994Concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were measured by h.p.l.c. in plasma and cerebrospinal fluid (CSF) samples from... (Clinical Trial)
Clinical Trial
Concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were measured by h.p.l.c. in plasma and cerebrospinal fluid (CSF) samples from 16 patients with cancer receiving oral (controlled-release) morphine. There was a close correlation between plasma and CSF morphine concentrations (r = 0.94, P = 0.0001) and both correlated with drug dosage (r = 0.61, P = 0.013 and r = 0.74, P = 0.0001, respectively). M3G and M6G in plasma and CSF were correlated (r = 0.81 and r = 0.82, both P = 0.0001). No relationship was apparent between M plus M6G concentrations in the CSF and pain scores.
Topics: Administration, Oral; Adult; Aged; Chromatography, High Pressure Liquid; Delayed-Action Preparations; Dose-Response Relationship, Drug; Female; Humans; Linear Models; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain; Pain Measurement
PubMed: 7826830
DOI: 10.1111/j.1365-2125.1994.tb04352.x -
Pharmacology, Biochemistry, and Behavior Mar 2007The main metabolite of morphine, morphine-3-glucuronide (M3G) has no opioid effects. Some studies have rather indicated that it antagonizes the antinociceptive and...
The main metabolite of morphine, morphine-3-glucuronide (M3G) has no opioid effects. Some studies have rather indicated that it antagonizes the antinociceptive and respiratory depressive effects of both morphine and the active metabolite morphine-6-glucuronide (M6G). We studied the possible influence of M3G on the psychostimulant properties of morphine and M6G measured by locomotor activity. Mice were given two injections, one with either 80, 240 or 500 micromol/kg M3G or saline followed by an injection of 20 or 30 micromol/kg morphine or M6G. M3G influenced the locomotor activity induced by both morphine and M6G, but in opposite directions. M3G reduced the morphine induced locomotor activity during the first hour following morphine injection in a concentration dependent manner. M3G pretreatment did not significantly influence brain concentrations of morphine indicating that the interaction was of a pharmacodynamic type. In contrast M3G pretreatment increased the M6G induced locomotor activity. M3G pretreatment increased serum and brain M6G concentrations to an extent indicating that this interaction was mainly of a pharmacokinetic type. In conclusion our results disclose complicated interactions between morphine and its two metabolites with respect to induction of locomotor activity and possibly also with respect to mechanisms related to drug reward.
Topics: Animals; Brain; Dose-Response Relationship, Drug; Drug Interactions; Male; Mice; Mice, Inbred C57BL; Morphine; Morphine Derivatives; Motor Activity; Reward
PubMed: 17343905
DOI: 10.1016/j.pbb.2007.02.001 -
European Journal of Pharmaceutical... Jan 2012The complete set of experimental microscopic partition coefficients of morphine was determined for the first time for any compound. The acid-base microequilibria were... (Comparative Study)
Comparative Study
The complete set of experimental microscopic partition coefficients of morphine was determined for the first time for any compound. The acid-base microequilibria were characterized by combining pH-potentiometry and deductive methods using auxiliary compounds of reduced complexity. The results show around three times as many non-charged than zwitterionic microspecies in aqueous solution. Partition of the individual microspecies was mimicked by model compounds of the closest possible similarity, then correction factors were determined and introduced. Thus the intrinsic partition coefficients of all the microspecies could be quantitated, including the non-charged and the zwitterionic ones. The non-charged microspecies is 1070 times as lipophilic as its zwitterionic protonation isomer. Their contribution ratio to the overall lipophilicity is 3090. The lipophilicity profile of morphine was expressed, calculated and depicted in terms of species-specific lipophilicities over the entire pH range.
Topics: Algorithms; Analgesics, Opioid; Anions; Cations; Codeine; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Morphine; Morphine Derivatives; Potentiometry
PubMed: 22120645
DOI: 10.1016/j.ejps.2011.11.007 -
British Journal of Pharmacology May 19921. The emetic potencies of morphine and its metabolite morphine 6-glucuronide have been determined in the ferret by constructing dose-response curves for mean total...
1. The emetic potencies of morphine and its metabolite morphine 6-glucuronide have been determined in the ferret by constructing dose-response curves for mean total retches and vomits for subcutaneous doses of 0.05 mg kg-1 to 5 mg kg-1. Morphine 6-glucuronide induced retching and vomiting at lower doses than morphine and at a maximal dose induced more retching and vomiting than morphine. 2. The emesis induced by both morphine and morphine 6-glucuronide was abolished by the preadministration of naloxone (0.5 mg kg-1 s.c.). 3. The 5-HT3 receptor antagonists granisetron and ondansetron (1 mg kg-1, s.c.) failed to abolish or reduce emesis induced by either compound. 4. At a high-dose (5 mg kg-1), morphine but not morphine 6-glucuronide failed to induce emesis and abolished the emesis induced by the cytotoxic drug, cyclophosphamide (200 mg kg-1, i.p.). 5. Preliminary pharmacokinetic studies of intravenous and subcutaneous morphine and morphine 6-glucuronide revealed that morphine 6-glucuronide accounts for less than 1% of the metabolic product of morphine in the ferret. Peak plasma levels of the two compounds after their subcutaneous administration were obtained within 10 min. The metabolic profile of morphine was not dose-dependent. There was no relationship between plasma level and emetic response for either compound.
Topics: Animals; Cyclophosphamide; Dose-Response Relationship, Drug; Emetics; Ferrets; Granisetron; Imidazoles; Indazoles; Injections, Subcutaneous; Morphine; Morphine Derivatives; Naloxone; Ondansetron; Vomiting
PubMed: 1324067
DOI: 10.1111/j.1476-5381.1992.tb14284.x -
Lancet (London, England) Dec 1948
Topics: Anesthesia; Anesthesiology; Atropine; Atropine Derivatives; Humans; Morphine; Morphine Derivatives; Premedication
PubMed: 18101999
DOI: 10.1016/s0140-6736(48)91604-3 -
Clinical Pharmacology and Therapeutics Sep 1990One hundred fifty-one patients with chronic cancer pain were studied during chronic treatment with oral morphine. Plasma concentrations of morphine and metabolites (M3G...
One hundred fifty-one patients with chronic cancer pain were studied during chronic treatment with oral morphine. Plasma concentrations of morphine and metabolites (M3G and M6G) were measured. The ratio of plasma morphine to metabolites was not affected by dose. Generalized linear interactive modeling analysis using morphine dose, age, sex, renal and hepatic dysfunction, and concomitant medication as explanatory variables accounted for 70% of the variance in plasma concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Increasing morphine dose was a significant factor for increased plasma concentrations of morphine, M3G, and M6G. Other significant factors were: age greater than 70 years (increased M3G and M6G plasma concentrations), plasma creatinine greater than 150 mumol/L (increased M3G and M6G plasma concentrations), male sex (decreased morphine and M6G plasma concentrations), raised creatinine plus coadministration of tricyclic antidepressants (increased M3G plasma concentrations), ranitidine (increased morphine plasma concentrations), and raised creatinine plus coadministration of ranitidine (increased M6G plasma concentrations).
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain; Sex Factors
PubMed: 2401122
DOI: 10.1038/clpt.1990.145 -
Pain Apr 1996Morphine, morphine-6-glucuronide (M6G) tolerance and cross-tolerance between morphine and M6G have been evaluated in mice. Daily administration of equipotent doses of...
Morphine, morphine-6-glucuronide (M6G) tolerance and cross-tolerance between morphine and M6G have been evaluated in mice. Daily administration of equipotent doses of M6G and morphine induced similar declines in antinociception over 9 days of treatment. However, a higher dose of M6G than morphine is required in tolerant animals to recover the initial response. In studies where daily morphine doses were substituted by M6G administration, on specific days, there was a significant fall in M6G antinociception on those days immediately following morphine administration, relative to the response to continued morphine (a decrease of 53.7% on day 2, P < 0.001 and a decrease of 62.5% on day 11, P < 0.05) and M6G (a decrease of 45.4% on day 2, P < 0.05) exposure. The decrease was independent of treatment duration and dosage. This decrease in the antinociceptive effect of M6G after morphine was avoided after clofibrate treatment, an inhibitor of (-)morphine metabolism. Determination of morphine and its metabolites in plasma revealed that morphine-3-glucuronide (M3G) concentration was significantly lower (P < 0.001) in animals treated with clofibrate (8.3 +/- 8.3 ng/ml) than in controls (422 +/- 80 ng/ml). The dose-response curve for M6G was shifted to the right by prior administration of M3G. These results suggest that during morphine treatment the antinociceptive effect of M6G may be antagonized by the other metabolite, M3G.
Topics: Analgesics, Opioid; Animals; Chromatography, High Pressure Liquid; Clofibrate; Dose-Response Relationship, Drug; Drug Tolerance; Hypolipidemic Agents; Injections, Subcutaneous; Male; Mice; Morphine; Morphine Derivatives; Pain Measurement
PubMed: 8826486
DOI: 10.1016/0304-3959(95)00198-0