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Drug Metabolism Reviews Aug 1996
Review
The disposition of morphine and its 3- and 6-glucuronide metabolites in humans and animals, and the importance of the metabolites to the pharmacological effects of morphine.
Topics: Animals; Biotransformation; Humans; Morphine; Morphine Derivatives; Narcotics
PubMed: 8875123
DOI: 10.3109/03602539608994011 -
JAMA Jul 2023
Topics: Europe; Morphine Derivatives; North America; Morphine; Internationality
PubMed: 37379016
DOI: 10.1001/jama.2023.11960 -
Clinical Pharmacokinetics Apr 1993Morphine, morphine-6-glucuronide (M6G), morphine-3-glucuronide (M3G) and normorphine were analysed with high performance liquid chromatography in plasma and urine,...
Morphine, morphine-6-glucuronide (M6G), morphine-3-glucuronide (M3G) and normorphine were analysed with high performance liquid chromatography in plasma and urine, collected over 72 h after administration of single intravenous 5 mg and oral 20 mg doses of morphine to 7 healthy volunteers. Systemic plasma clearance of morphine was on average 21.1 +/- 3.4 ml/min/kg (1.27 +/- 0.20 L/h/kg), volume of distribution was 2.9 +/- 0.8 L/kg and oral bioavailability was 29.2 +/- 7.2%. Clearance of morphine to form M3G and M6G comprised 57.3% and 10.4%, respectively, and renal clearance comprised 10.9% of total systemic plasma clearance; hence, more than one-fifth of a dose (20.8%) remained as unidentified residual clearance. On the basis of the area under the plasma concentration-time curves determined after oral and intravenous administration, the ratios of M6G:morphine were 3.6 +/- 1.2 and 0.7 +/- 0.3, respectively. The corresponding figures for M3G:morphine were 29.9 +/- 6.8 and 7.7 +/- 1.4. Differences in metabolic ratios between the parenteral and oral routes could be attributed solely to differences in morphine concentrations as evidenced both by plasma concentrations and amounts excreted in urine. An oral:parenteral potency ratio of 1:3 may, thus, be due to differences in circulating amounts of morphine since the proportions of an administered dose found as M6G and M3G after administration by both routes were equal. A major finding was a slowly declining terminal phase of morphine and metabolites that was evident both in plasma and in urinary excretion versus time curves, where the half-lives of morphine, M3G and M6G were 15.1 +/- 6.5 h, 11.2 +/- 2.7 h and 12.9 +/- 4.5 h, respectively. The terminal half-life of normorphine was 23.9 +/- 10.1 h after oral administration. Comparison of oral with intravenous excretion curves showed that a greater part of morphine and metabolites were excreted during the slowly declining phase after the oral dose than the intravenous dose, which is highly suggestive of enterohepatic cycling. The renal clearance of M6G and morphine was seen to exceed creatinine clearance, possibly due to an active secretion process.
Topics: Administration, Oral; Adult; Enterohepatic Circulation; Female; Humans; Injections, Intravenous; Male; Middle Aged; Morphine; Morphine Derivatives
PubMed: 8491060
DOI: 10.2165/00003088-199324040-00007 -
The Annals of Pharmacotherapy Dec 2001To investigate the effects of major thermal burn injury and continuous intravenous morphine infusion on the disposition of morphine and its glucuronidated metabolites,...
OBJECTIVE
To investigate the effects of major thermal burn injury and continuous intravenous morphine infusion on the disposition of morphine and its glucuronidated metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) once a week for three weeks.
CASE SUMMARIES
Five patients with major first-, second-, or third-degree burn injuries received long-term intravenous morphine infusion. The required dose varied greatly (from 4 to 39.5 mg/h). The steady-state concentrations of morphine, M3G, and M6G ranged from 20 to 452, 29 to 3436, and 20 to 1240 mumol/L, respectively. The systemic clearance (Cls) of morphine ranged from 14.8 to 40.3 mL/min/kg and did not change over time. The ratios of M6G and M3G to morphine were not affected by dose, even with the wide variation of intravenous dosage. Morphine kinetics appeared to be first-order. Mean recovery of morphine, M3G, and M6G in urine was 1.7 +/- 1.0%, 42.0 +/- 16.8%, and 11.8 +/- 3.2%, respectively, and renal clearance ranged from 8 to 64, 26 to 325, and 59 to 589 mL/min, respectively. Mean pain intensity ratings at rest remained low and stable (0.7 +/- 0.9 on day 7, 0.4 +/- 0.3 on day 14, 0 +/- 0 on day 21).
DISCUSSION
To our knowledge, this is the first published report describing morphine, M3G, and M6G disposition in patients with major thermal burn injury. The Cls of morphine is similar to that observed in other patient populations and healthy subjects, suggesting that the presence of major burn injuries or a continuous morphine infusion over a three-week period may not contribute significantly to the variability among individuals. In these cases, the renal clearance of morphine and its glucuronides was within the range of values reported for other populations of patients and healthy subjects. Recovery of morphine and its glucuronides in urine was also similar to that in healthy individuals.
CONCLUSIONS
These cases suggest that the effects of major burn injuries and of long-term intravenous infusion of morphine did not seem to modify morphine, M3G, and M6G disposition. Among patients with burn injuries, the severity of burns of duration of administration are not a cause of nonlinear kinetic of morphine or of morphine resistance. The morphine infusion rate was substantially variable and not directly related to its clearance, suggesting that monitoring of morphine should be focused on the clinical response.
Topics: Adult; Analgesics, Opioid; Burns; Chromatography, High Pressure Liquid; Female; Humans; Infusions, Intravenous; Liver Function Tests; Male; Metabolic Clearance Rate; Middle Aged; Morphine; Morphine Derivatives
PubMed: 11793627
DOI: 10.1345/aph.10251 -
British Journal of Anaesthesia Oct 1989Plasma and urine concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide were measured in seven patients after orthotopic liver transplantation....
Plasma and urine concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide were measured in seven patients after orthotopic liver transplantation. After a single i.v. bolus of morphine sulphate 10 mg a biexponential decay was observed. Although the distribution and elimination half-lives for morphine were similar to those described in previous studies, a greater total apparent volume of distribution was observed. This was reflected in a greater plasma clearance of morphine than has been reported previously. The concentration of morphine glucuronides remained increased 24 h after administration of morphine; the clinical significance of this remains to be established. The metabolism of morphine was virtually complete, with 4.5% unchanged morphine recovered in urine 24 h after drug administration.
Topics: Adult; Female; Humans; Liver Circulation; Liver Transplantation; Male; Middle Aged; Morphine; Morphine Derivatives
PubMed: 2818915
DOI: 10.1093/bja/63.4.375 -
British Journal of Anaesthesia May 1990
Topics: Adolescent; Critical Care; Female; Humans; Morphine; Morphine Derivatives; Polyradiculoneuropathy; Time Factors
PubMed: 2354106
DOI: 10.1093/bja/64.5.649-a -
FEBS Letters Mar 2000Morphine-3- and morphine-6-glucuronide are morphine's major metabolites. As morphine-6-glucuronide produces stronger analgesia than morphine, we investigated the effects... (Comparative Study)
Comparative Study
Morphine-3- and morphine-6-glucuronide are morphine's major metabolites. As morphine-6-glucuronide produces stronger analgesia than morphine, we investigated the effects of acute and chronic morphine glucuronides on adenylyl cyclase (AC) activity. Using COS-7 cells cotransfected with representatives of the nine cloned AC isozymes, we show that AC-I and V are inhibited by acute morphine and morphine-6-glucuronide, and undergo superactivation upon chronic exposure, while AC-II is stimulated by acute and inhibited by chronic treatment. Morphine-3-glucuronide had no effect. The weak opiate agonists codeine and dihydrocodeine are also addictive. These opiates, in contrast to their 3-O-demethylated metabolites morphine and dihydromorphine (formed by cytochrome P450 2D6), demonstrated neither acute inhibition nor chronic-induced superactivation. These results suggest that metabolites of morphine (morphine-6-glucuronide) and codeine/dihydrocodeine (morphine/dihydromorphine) may contribute to the development of opiate addiction.
Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; CHO Cells; Codeine; Cricetinae; Dihydromorphine; Dose-Response Relationship, Drug; Enzyme Activation; Isoenzymes; Morphine; Morphine Derivatives; Opioid-Related Disorders; Receptors, Opioid, mu; Thyrotropin; Transfection
PubMed: 10745087
DOI: 10.1016/s0014-5793(00)01329-6 -
Biology of the Neonate Dec 1999The study of chronic in utero exposure to heroin and morphine in the human is limited by polysubstance abuse. The guinea pig was used as a model for the human to...
The study of chronic in utero exposure to heroin and morphine in the human is limited by polysubstance abuse. The guinea pig was used as a model for the human to determine the in vivo and in vitro effect of chronic morphine exposure on morphine metabolism in the pregnant dam and her offspring. In vivo pharmacokinetics of morphine were examined in pregnant guinea pigs following pretreatment with either saline or morphine. In vitro hepatic enzyme kinetics were also examined in a similar group of pregnant dams and their fetuses. Additional pregnant dams were allowed to give birth and their pups' enzyme kinetics were studied at 1, 3, and 7 days. Apparent V(MAX) for the formation of both morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) formation was significantly increased in the morphine-treated pregnant guinea pig. However, no effect of morphine treatment was detectable on the in vivo pharmacokinetics of morphine in the pregnant dam. The apparent morphine K(M) for the formation of M3G was significantly different than the apparent K(M) for the formation of M6G. Significant age effects on the enzyme kinetics were found. The apparent V(MAX) for the formation of both glucuronides increased through the neonatal period. Through literature comparisons, the guinea pig was shown to have in vivo pharmacokinetics similar to the pregnant human, and the guinea pig pups were found to have enzyme development consistent with in vivo pharmacokinetic development seen in human neonates, infants and children.
Topics: Animals; Female; Guinea Pigs; Kinetics; Maternal-Fetal Exchange; Morphine; Morphine Derivatives; Pregnancy
PubMed: 10567765
DOI: 10.1159/000014180 -
Journal of Analytical Toxicology Sep 1997Morphine, morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), and 6-monoacetylmorphine (6-MAM) were isolated from body fluids using solid-phase extraction and...
Morphine, morphine-3-glucuronide, morphine-6-glucuronide, and 6-monoacetylmorphine determined by means of atmospheric pressure chemical ionization-mass spectrometry-liquid chromatography in body fluids of heroin victims.
Morphine, morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), and 6-monoacetylmorphine (6-MAM) were isolated from body fluids using solid-phase extraction and determined by means of atmospheric pressure chemical ionization-mass spectrometry-liquid chromatography (APCI-LC-MS) in selected ion monitoring mode. The following ions were monitored: m/z 286 for morphine; m/z 286 and 462 for M3G and M6G; m/z 211, 268, and 328 for 6-MAM; and m/z 289 for morphine-d3 (internal standard). The recoveries ranged from 82 to 89% The limits of detection were as follows: 0.1 ng/mL (morphine), 0.5 ng/mL (6-MAM), and 1 ng/mL (M3G and M6G). The analytes were determined in samples taken from 21 heroin-overdose victims. Twenty-one blood samples, 11 cerebrospinal fluid (CSF) samples, 12 vitreous humor (VH) samples, and 6 urine samples were investigated. Blood concentrations (ng/mL) of morphine ranged from 8 to 1539, of M3G from 111 to 941, of M6G from 32 to 332, and of 6-MAM from 0 to 73. The levels of morphine were correlated with glucuronide values and with 6-MAM. The concentrations of morphine, M3G, and M6G in CSF were, as a rule, lower than in blood and lower in VH than in CSF. The concentrations of morphine and molar ratios of M6G-morphine in blood and CSF were correlated. Low ratios of M3G-morphine and M6G-morphine in blood of heroin-overdose victims indicated short survival time after drug intake.
Topics: Adolescent; Adult; Atmospheric Pressure; Autopsy; Chromatography, Liquid; Female; Heroin; Heroin Dependence; Humans; Male; Mass Spectrometry; Morphine; Morphine Derivatives; Narcotics; Urine; Vitreous Body
PubMed: 9288586
DOI: 10.1093/jat/21.5.346 -
[Analgesic effect of morphine and its metabolites administered by an intracerebroventricular route].Bulletin de L'Academie Nationale de... Jun 1995Intraventricular morphine administration is indicated, in some selected cases, to alleviate intractable cancer pain. Our pharmacokinetics data in cerebro-spinal fluid... (Review)
Review
Intraventricular morphine administration is indicated, in some selected cases, to alleviate intractable cancer pain. Our pharmacokinetics data in cerebro-spinal fluid allowed us to formulate the theory of "Front de Recrutement". Then we were able to determine in cisternal and ventricular cerebrospinal fluid the morphine 6-glucuronide concentrations. Morphine 6-glucuronide is the main analgesic metabolite of morphine and its presence in cerebro-spinal fluid could be due to a metabolism of morphine in the central nervous system. Our animal studies showed that the analgesic activity of morphine 6-glucuronide was 27 to 67 times higher than that of morphine. By demonstrating the 6-monoacetyl morphine potency (analgesic metabolite of heroin that is 20 times more potent than morphine), we showed the involvement of the 6 position in the analgesic effect of these opioids. When we compared the morphine-6 concentrations in human cerebro-spinal fluid with the analgesic potency of this metabolite, the morphine-6 glucuronide was responsible of 33% to 67% of the supra-spinal analgesic effect. As heroin, morphine must be considered as a precursor whose metabolites have pharmacologic effects.
Topics: Analgesics, Opioid; Animals; Humans; Injections, Intraventricular; Morphine; Morphine Derivatives
PubMed: 8542351
DOI: No ID Found