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Maree T. Smith - One of the best experts on this subject based on the ideXlab platform.
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Comparative studies of the neuro-excitatory behavioural effects of Morphine-3-Glucuronide and dynorphin A(2-17) following spinal and supraspinal routes of administration
Pharmacology biochemistry and behavior, 2009Co-Authors: K. Hemstapat, Stephen R. Edwards, Maree T. SmithAbstract:Morphine-3-Glucuronide (M3G) administered centrally produces dose-dependent neuro-excitatory behaviours in rodents via a predominantly non-opioid mechanism. The endogenous opioid peptide, dynorphin A (Dyn A) (1-17), is rapidly cleaved in vivo to the relatively more stable fragment Dyn A(2-17) which also produces excitatory behaviours in rodents via a non-opioid mechanism. This study investigated the possible contribution of Dyn A(2-17) to the neuro-excitatory behaviours evoked by supraspinally and spinally administered M3G in male Sprague-Dawley (SD) rats. Marked qualitative differences in behaviours were apparent following administration of M3G and Dyn A(2-17). Administration of 11 nmol i.c.v. doses of M3G produced intermittent myoclonic jerks, tonic-clonic convulsions, and ataxia, as well as postural changes, whereas i.c.v. Dyn A(2-17) at 15 nmol produced effects on body posture alone. Administration of 11 nmol i.t. doses of M3G produced intermittent explosive motor activity, and touch-evoked agitation, as well as postural changes, whereas i.t. Dyn A(2-17) at 15 nmol produced postural changes, touch-evoked agitation, and paralysis. Pre-treatment with Dyn A antiserum (200 microg) markedly attenuated total behavioural excitation following i.c.v. and i.t. administration of Dyn A(2-17) by approximately 94% and 78%, respectively. However, total behavioural excitation following i.c.v. and i.t. administration of M3G was less markedly attenuated (both approximately 27%) by pre-treatment with Dyn A antiserum, with reductions in tonic-clonic convulsions ( approximately 43%), explosive motor behaviour ( approximately 28%), and touch-evoked agitation ( approximately 22%). The present findings discount a major role for Dyn A in mediating the neuro-excitatory effects of M3G, although it may contribute to maintaining some individual neuro-excitatory behaviours.
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Simultaneous determination of Morphine, oxycodone, Morphine-3-Glucuronide, and noroxycodone concentrations in rat serum by high performance liquid chromatography-electrospray ionization-tandem mass spectrometry.
Journal of Chromatography B, 2005Co-Authors: Stephen R. Edwards, Maree T. SmithAbstract:An assay using high performance liquid chromatography (HPLC)-electrospray ionization-tandem mass spectrometry (ESI-MS-MS) was developed for simultaneously determining concentrations of Morphine, oxycodone, Morphine-3-Glucuronide, and noroxycodone, in 50 mul samples of rat serum. Deuterated (d(3)) analogues of each compound were used as internal standards. Samples were treated with acetonitrile to precipitate plasma proteins: acetonitrile was removed from the supernatant by centrifugal evaporation before analysis. Limits of quantitation (ng/ml) and their between-day accuracy and precision (%deviation and %CV) were-Morphine, 3.8 (4.3% and 7.6%); Morphine-3-Glucuronide, 5.0 (4.5% and 2.9%); oxycodone, 4.5 (0.4% and 9.3%); noroxycodone, 5.0 (8.5% and 4.6%). (C) 2004 Elsevier B.V. All rights reserved.
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Morphine-3-Glucuronide's neuro-excitatory effects are mediated via indirect activation of N-methyl-D-aspartic acid receptors: mechanistic studies in embryonic cultured hippocampal neurones.
Anesthesia & Analgesia, 2003Co-Authors: K. Hemstapat, Gregory R. Monteith, Deborah Smith, Maree T. SmithAbstract:Indirect evidence indicates that Morphine-3-Glucuronide (M3G) may contribute significantly to the neuro-excitatory side effects (myoclonus and allodynia) of large-dose systemic Morphine. To gain insight into the mechanism underlying M3G' s excitatory behaviors, We used fluo-3 fluorescence digital imaging techniques to assess the acute effects of M3G (5-500 muM) on the cytosolic calcium concentration ([Ca2+](CYT)) in cultured embryonic hippocampal neurones. Acute (3 min) exposure of neurones to M3G evoked [Ca2+](CYT) transients that were typically either (a) transient oscillatory responses characterized by a rapid increase in [Ca2+](CYT) oscillation amplitude that was sustained for at least similar to30 s or (b) a sustained increase in [Ca2+](CYT) that slowly recovered to baseline. Naloxone-pretreatment decreased the proportion of M3G-responsive neurones by 10%-25%, implicating a predominantly non-opioidergic mechanism. Although the naloxone-insensitive M3G-induced increases in [Ca2+](CYT) were completely blocked by N-methyl-D-aspartic acid (NMDA) antagonists and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (alphaamino-3-hydroxy-5-methyl-4-isoxazolepropiordc acid/ kainate antagonist), CNQX did not block the large increase in [Ca2+](CYT) evoked by NMDA (as expected), confirming that N13G indirectly activates the NMDA receptor. Additionally, tetrodotoxin (Na+ channel blocker), baclofen (gamma-aminobutyric acid, agonist), MVIIC (P/Q-type calcium channel blocker), and nifedipine (L-type calcium channel blocker) all abolished M3G-induced increases in [Ca2+](CYT), suggesting that M3G may produce its neuro-excitatory effects by modulating neurotransmitter release. However, additional characterization is required.
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Hydromorphone-3-Glucuronide: a more potent neuro-excitant than its structural analogue, Morphine-3-Glucuronide.
Life sciences, 2001Co-Authors: Andrew W. E. Wright, Laurence E. Mather, Maree T. SmithAbstract:In humans, hydromorphone (HMOR) is metabolised principally by conjugation with glucuronic acid to form hydromorphone-3-Glucuronide (H3G), a close structural analogue of Morphine-3-Glucuronide (M3G), the major metabolite of Morphine. In a previous study we described the biochemical synthesis of H3G together with a preliminary evaluation of its pharmacology which revealed that it is a neuroexcitant in rats in a manner analogous to M3G. Thus the aims of the current study were to quantify the neuro-excitatory behaviours evoked by intracerebroventricular (icv) H3G in the rat and to define its potency relative to M3G. Groups of adult male Sprague-Dawley rats received icv injections (1 microL) of H3G (1 - 3 microg), M3G (2 - 7 microg) or vehicle via a stainless steel guide cannula that had been implanted stereotaxically seven days prior to drug administration. Behavioural excitation was monitored by scoring fifteen different behaviours (myoclonic jerks, chewing, wet-dog-shakes, rearing, tonic-clonic-convulsions, explosive motor behaviour, grooming, exploring, general activity, eating, staring, ataxia, righting reflex, body posture, touch evoked agitation) immediately prior to icv injection and at the following post-dosing times: 5, 15, 25, 35, 50, 65 and 80 min. H3G produced dose-dependent behavioural excitation in a manner analogous to that reported previously for M3G by our laboratory and reproduced herein. H3G was found to be approximately 2.5-fold more potent than M3G, such that the mean (+/- S.D.) ED50 values were 2.3 (+/- 0.1) microg and 6.1 (+/- 0.6) microg respectively. Thus, our data clearly imply that if H3G crosses the BBB with equivalent efficiency to M3G, then the myoclonus, allodynia and seizures observed in some patients dosed chronically with large systemic doses of HMOR, are almost certainly due to the accumulation of sufficient H3G in the central nervous system, to evoke behavioural excitation.
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Brain region-specific studies of the excitatory behavioral effects of Morphine-3-Glucuronide
Life sciences, 1999Co-Authors: Andrew J. Halliday, Selena E Bartlett, Paul B. Colditz, Maree T. SmithAbstract:This study was designed to determine in rats whether Morphine-3-Glucuronide (M3G) produces its neuro-excitatory effects most potently in the ventral hippocampus (as has been reported previously for subanalgesic doses of opioid peptides). Guide cannulae were implanted into one of seven regions of the rat brain: lateral ventricle; ventral, CA1 and CA2-CA3 regions of the hippocampus; amygdala; striatum or cortex. After a 7 day recovery period, rats received intracerebral injections of (i) M3G (1.1 or 11 nmol) (ii) DADLE ([D-Ala2,D-Leu5]enkephalin), (45 nmol, positive controls) or (iii) vehicle (deionised water), and behavioral excitation was quantified over 80 min. High-dose M3G (11 nmol) evoked behavioral excitation in all brain regions but the onset, severity and duration of these effects varied considerably among brain regions. By contrast, low-dose M3G (1.1 nmol) evoked excitatory behaviors only when administered into the ventral hippocampus and the amygdala, with the most potent effects being observed in the ventral hippocampus. Prior administration of the nonselective opioid antagonists, naloxone and beta-funaltrexamine into the ventral hippocampus, markedly attenuated low-dose M3G's excitatory effects but did not significantly alter levels of excitation evoked by high-dose M3G. Naloxone given 10 min after M3G (1.1 or 11 nmol) did not significantly attenuate behavioral excitation. Thus, M3G's excitatory behavioral effects occur most potently in the ventral hippocampus as reported previously for subanalgesic doses of opioid peptides, and appear to be mediated through at least two mechanisms, one possibly involving excitatory opioid receptors and the other, non-opioid receptors.
Roger L Nation - One of the best experts on this subject based on the ideXlab platform.
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application of a loading wash out method for investigating the hepatocellular efflux of a hepatically generated metabolite Morphine 3 Glucuronide
Journal of Pharmacy and Pharmacology, 1999Co-Authors: Allan M. Evans, Josephine A Obrien, Roger L NationAbstract:Previous studies using the rat isolated perfused liver demonstrated that the hepatic disposition of Morphine-3-Glucuronide is membrane permeability-rate limited, and that the movement of the metabolite across hepatic sinusoidal and canalicular membranes is partly via carrier-mediated transport systems. As a consequence of the membrane permeability-limitation, the biliary excretion of hepatically-generated Morphine-3-Glucuronide is much more efficient than that of Morphine-3-Glucuronide reaching the liver via the vasculature. We have quantitated the cellular efflux kinetics (cell-to-blood and cell-to-bile) of Morphine-3-Glucuronide in the rat isolated perfused liver using a loading wash-out design. In the 'loading' phase, Morphine was infused into the liver (2.7 microM) and the biliary excretion and sinusoidal efflux of Morphine-3-Glucuronide was assessed under steady-state conditions. Subsequently, the infusion was stopped and the concentration vs time profile of Morphine-3-Glucuronide in outflow perfusate (the wash-out phase) was determined. A physiologically-based pharmacokinetic model was used to determine the rate-constants for the movement of hepatically-generated Morphine-3-Glucuronide into the sinusoidal and canalicular spaces of the liver, and the associated membrane permeability terms. The mean (+/-s.d.) rate constants for the biliary excretion and sinusoidal efflux of Morphine-3-Glucuronide were determined to be 0.160 +/- 0.043 and 0.169 +/- 0.068 min(-1), respectively, and the corresponding membrane permeability parameters were 1.12 and 1.18 mL min(-1), respectively. The sinusoidal membrane permeability term was significantly less than hepatic blood flow in the rat. The volume of distribution of hepatically-generated Morphine-3-Glucuronide (207.5 +/- 74.8 mL) was found to be approximately 50-times the intracellular space of the rat liver, suggesting that hepatically-generated Morphine-3-Glucuronide accumulates within hepatocytes. The results indicate that hepatically-generated Morphine-3-Glucuronide undergoes intracellular accumulation, probably as a consequence of poor membrane permeability.
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Application of a Loading Wash‐out Method for Investigating the Hepatocellular Efflux of a Hepatically‐generated Metabolite, Morphine‐3‐Glucuronide
Journal of Pharmacy and Pharmacology, 1999Co-Authors: Allan M. Evans, Josephine A. O'brien, Roger L NationAbstract:Previous studies using the rat isolated perfused liver demonstrated that the hepatic disposition of Morphine-3-Glucuronide is membrane permeability-rate limited, and that the movement of the metabolite across hepatic sinusoidal and canalicular membranes is partly via carrier-mediated transport systems. As a consequence of the membrane permeability-limitation, the biliary excretion of hepatically-generated Morphine-3-Glucuronide is much more efficient than that of Morphine-3-Glucuronide reaching the liver via the vasculature. We have quantitated the cellular efflux kinetics (cell-to-blood and cell-to-bile) of Morphine-3-Glucuronide in the rat isolated perfused liver using a loading wash-out design. In the 'loading' phase, Morphine was infused into the liver (2.7 microM) and the biliary excretion and sinusoidal efflux of Morphine-3-Glucuronide was assessed under steady-state conditions. Subsequently, the infusion was stopped and the concentration vs time profile of Morphine-3-Glucuronide in outflow perfusate (the wash-out phase) was determined. A physiologically-based pharmacokinetic model was used to determine the rate-constants for the movement of hepatically-generated Morphine-3-Glucuronide into the sinusoidal and canalicular spaces of the liver, and the associated membrane permeability terms. The mean (+/-s.d.) rate constants for the biliary excretion and sinusoidal efflux of Morphine-3-Glucuronide were determined to be 0.160 +/- 0.043 and 0.169 +/- 0.068 min(-1), respectively, and the corresponding membrane permeability parameters were 1.12 and 1.18 mL min(-1), respectively. The sinusoidal membrane permeability term was significantly less than hepatic blood flow in the rat. The volume of distribution of hepatically-generated Morphine-3-Glucuronide (207.5 +/- 74.8 mL) was found to be approximately 50-times the intracellular space of the rat liver, suggesting that hepatically-generated Morphine-3-Glucuronide accumulates within hepatocytes. The results indicate that hepatically-generated Morphine-3-Glucuronide undergoes intracellular accumulation, probably as a consequence of poor membrane permeability.
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Comparison of the disposition of hepatically-generated Morphine-3-Glucuronide and Morphine-6-Glucuronide in isolated perfused liver from the guinea pig.
Pharmaceutical Research, 1997Co-Authors: Robert W. Milne, Rikke Holm Jensen, Allan M. Evans, Claus Larsen, Roger L NationAbstract:Purpose. Humans and guinea pigs metabolise Morphine extensively, forming the isomers Morphine-3-Glucuronide (M3G) and Morphine-6-Glucuronide (M6G) in relatively similar ratios. Both metabolites are formed in the liver, and their greater polarity relative to the parent aglycone may limit their permeability across hepatic membranes. This study compared the disposition of hepatically-generated M3G and M6G in perfused livers isolated from guinea pigs.
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Influence of Renal Failure on the Disposition of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Sheep during Intravenous Infusion with Morphine
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Robert W. Milne, C F Mclean, A J Rutten, L.e. Mather, Roger L Nation, William B. Runciman, Andrew A. SomogyiAbstract:The influence of experimentally induced renal failure on the disposition of Morphine, Morphine-3-Glucuronide (M3G) and Morphine-6-Glucuronide (M6G) was examined in seven sheep infused intravenously with Morphine for 6 hr. Between 5 and 6 hr, blood was collected from the aorta, pulmonary artery, hepatic, hepatic portal and renal veins and posterior vena cava. Additional samples from the aorta and urine were collected up to 144 hr. Morphine, M3G and M6G were determined in plasma and urine by high-performance liquid chromatography. Constant concentrations of Morphine, but not of M3G and M6G, were achieved in plasma between 5 and 6 hr. Significant (P < .001) extraction of Morphine by the liver (0.72 ± 0.05) and kidney (0.42 ± 0.15) occurred. Compared with sheep with normal kidneys ([Milne et al. , 1995][1]), renal failure did not alter (P = .11) the mean total clearance of Morphine (1.5 ± 0.3 liters/min); clearance by the kidney was less (P < .001). However, a paired comparison using sheep common to this study and from the study when their kidneys were normal revealed a significant reduction in mean total clearance of 25%. The renal extraction of M3G and M6G and urinary recovery of the dose as summed Morphine, M3G and M6G were reduced by renal failure. The kidney metabolized Morphine to M3G. The data suggest that nonrenal elimination of M3G becomes more important during renal failure. [1]: #ref-9
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effects of albumin on the disposition of Morphine and Morphine 3 Glucuronide in the rat isolated perfused liver
Clinical and Experimental Pharmacology and Physiology, 1997Co-Authors: Josephine A Obrien, Allan M. Evans, Roger L NationAbstract:1. The effect of albumin on the disposition of Morphine and hepatically generated Morphine-3-Glucuronide (M3G) was investigated in the single-pass rat isolated perfused liver. 2. Using a balanced cross-over design, each of 10 livers was perfused at 30 mL/min with medium containing 2.7 mumol/L Morphine in the presence and absence of 10 g/L bovine serum albumin (BSA). 3. Both bile flow rate and hepatic oxygen consumption were significantly higher (P 0.05) by the presence or absence of BSA. 6. The fraction of Morphine escaping heptic extraction in the absence of BSA (mean +/- SD; 0.41 +/- 0.14) was not altered significantly (P > 0.05) by the presence of the protein in perfusate (0.35 +/- 0.13), indicating no change in the intrinsic clearance or Morphine despite the difference in oxygen consumption. 7. The fraction of hepatically generated M3G excreted in bile was significantly higher (P < 0.005) when BSA was present in the perfusate than when it was not (0.44 +/- 0.14 vs 0.38 +/- 0.16, respectively). 8. The results are consistent with the concept that BSA modifies the ability of solutes, including M3G, to move through the paracellular pathway from the canalicular to the vascular space. 9. It is concluded that because albumin may modify not only the unbound fraction of a ligand in perfusate, but also the functional performance of the liver, care is needed in the interpretation of studies examining the influence of the protein on the hepatic disposition of drugs and their metabolites.
Andrew A. Somogyi - One of the best experts on this subject based on the ideXlab platform.
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Influence of Renal Failure on the Disposition of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Sheep during Intravenous Infusion with Morphine
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Robert W. Milne, C F Mclean, A J Rutten, L.e. Mather, Roger L Nation, William B. Runciman, Andrew A. SomogyiAbstract:The influence of experimentally induced renal failure on the disposition of Morphine, Morphine-3-Glucuronide (M3G) and Morphine-6-Glucuronide (M6G) was examined in seven sheep infused intravenously with Morphine for 6 hr. Between 5 and 6 hr, blood was collected from the aorta, pulmonary artery, hepatic, hepatic portal and renal veins and posterior vena cava. Additional samples from the aorta and urine were collected up to 144 hr. Morphine, M3G and M6G were determined in plasma and urine by high-performance liquid chromatography. Constant concentrations of Morphine, but not of M3G and M6G, were achieved in plasma between 5 and 6 hr. Significant (P < .001) extraction of Morphine by the liver (0.72 ± 0.05) and kidney (0.42 ± 0.15) occurred. Compared with sheep with normal kidneys ([Milne et al. , 1995][1]), renal failure did not alter (P = .11) the mean total clearance of Morphine (1.5 ± 0.3 liters/min); clearance by the kidney was less (P < .001). However, a paired comparison using sheep common to this study and from the study when their kidneys were normal revealed a significant reduction in mean total clearance of 25%. The renal extraction of M3G and M6G and urinary recovery of the dose as summed Morphine, M3G and M6G were reduced by renal failure. The kidney metabolized Morphine to M3G. The data suggest that nonrenal elimination of M3G becomes more important during renal failure. [1]: #ref-9
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Influence of Renal Failure on the Disposition of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Sheep during Intravenous Infusion with Morphine
The Journal of pharmacology and experimental therapeutics, 1997Co-Authors: Robert W. Milne, C F Mclean, A J Rutten, Roger L Nation, William B. Runciman, Laurence E. Mather, Andrew A. SomogyiAbstract:The influence of experimentally induced renal failure on the disposition of Morphine, Morphine-3-Glucuronide (M3G) and Morphine-6-Glucuronide (M6G) was examined in seven sheep infused intravenously with Morphine for 6 hr. Between 5 and 6 hr, blood was collected from the aorta, pulmonary artery, hepatic, hepatic portal and renal veins and posterior vena cava. Additional samples from the aorta and urine were collected up to 144 hr. Morphine, M3G and M6G were determined in plasma and urine by high-performance liquid chromatography. Constant concentrations of Morphine, but not of M3G and M6G, were achieved in plasma between 5 and 6 hr. Significant (P < .001) extraction of Morphine by the liver (0.72 +/- 0.05) and kidney (0.42 +/- 0.15) occurred. Compared with sheep with normal kidneys (Milne et al., 1995), renal failure did not alter (P = .11) the mean total clearance of Morphine (1.5 +/- 0.3 liters/min); clearance by the kidney was less (P < .001). However, a paired comparison using sheep common to this study and from the study when their kidneys were normal revealed a significant reduction in mean total clearance of 25%. The renal extraction of M3G and M6G and urinary recovery of the dose as summed Morphine, M3G and M6G were reduced by renal failure. The kidney metabolized Morphine to M3G. The data suggest that nonrenal elimination of M3G becomes more important during renal failure.
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Comparative disposition of Morphine-3-Glucuronide during separate intravenous infusions of Morphine and Morphine-3-Glucuronide in sheep. Importance of the kidney.
Drug Metabolism and Disposition, 1995Co-Authors: Robert W. Milne, C F Mclean, A J Rutten, L.e. Mather, Roger L Nation, William B. Runciman, Andrew A. SomogyiAbstract:The disposition of Morphine-3-Glucuronide (M3G) in sheep was compared during separate constant infusions of Morphine and M3G. Five ewes received a 15-min loading dose, followed by a constant infusion of Morphine sulfate (10 mg/hr) or M3G (4 mg/hr for 4 sheep, 7.5 mg/hr for 1 sheep) for a further 5.75 hr. During the 5th-6th hr of infusion, blood was collected simultaneously from the aorta, pulmonary artery, hepatic vein, hepatic portal vein, renal vein, and posterior vena cava. Additional samples were collected from the aorta from 0 to 5 hr and from 6 to 48 hr. Urine was collected via an indwelling catheter from 0 to 6 hr, with further free-flowing urine up to 48 hr. An HPLC assay was used to determine simultaneously Morphine, M3G, and Morphine-6-Glucuronide (M6G) in plasma and urine. Constant concentrations of Morphine, M3G, and M6G in plasma were achieved during the 5- to 6-hr period of infusion with Morphine, as were the concentrations of M3G while M3G was infused. Regional net extraction ratios and total and regional clearances were calculated during the 5- to 6-hr period. After the infusions were ceased, there was prolonged elimination of M3G formed in situ from Morphine compared to when infused as M3G. No Morphine or M6G was detected in the plasma during and after infusion with M3G, nor were they found in urine collected up to 6 hr.(ABSTRACT TRUNCATED AT 250 WORDS)
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Plasma Concentrations and Renal Clearance of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Cancer Patients Receiving Morphine
Clinical Pharmacokinectics, 1993Co-Authors: Andrew A. Somogyi, Charles L. M. Olweny, Panagiotis Tsirgiotis, James F. Cleary, Catherine Danz, Jacoba T Van Crugten, Robert W. Milne, Roger L Nation, Felix BochnerAbstract:The plasma concentrations and renal clearance values of Morphine, Morphine-3-Glucuronide (M3G) and Morphine-6-Glucuronide (M6G) were determined in 11 adult cancer patients maintained on a long term oral Morphine dosage (10 to 100mg every 4h). Concentrations in plasma and urine were determined by a specific high performance liquid chromatography assay. In this group of patients, whose creatinine clearance values ranged from 52 to 180 ml/min (3.12 to 10.8 L/h), average steady-state plasma concentrations of Morphine, M3G and M6G were related (p < 0.01) to the Morphine dose per kilogram of bodyweight. The mean total urinary recovery as Morphine, M3G and M6G was 74.6 ± 26.5% of the dose. Renal clearance values for M3G and M6G were closely related (r2 = 0.80; p < 0.0005). It was not possible to detect a relationship between the renal clearance of Morphine, M3G and M6G, and that of creatinine. The renal tubular handling of all 3 compounds showed wide interindividual variation, and there was evidence of either net renal tubular secretion or reabsorption. There was no apparent relationship between plasma Morphine and M6G concentrations and pain relief.
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Renal tubular transport of Morphine, Morphine-6-Glucuronide, and Morphine-3-Glucuronide in the isolated perfused rat kidney.
Drug Metabolism and Disposition, 1991Co-Authors: Jacoba T Van Crugten, Benedetta C Sallustio, Roger L Nation, Andrew A. SomogyiAbstract:The isolated perfused rat kidney was used to examine the renal handling of Morphine and its inactive metabolite Morphine-3-Glucuronide (M3G), and active metabolite Morphine-6-Glucuronide (M6G). The kidneys were perfused with Krebs-Henseleit buffer (pH 7.4) containing albumin, glucose, and amino acids, and drug concentrations were measured by high performance liquid chromatography. There was no conversion of Morphine to the Glucuronides or deconjugation of M3G or M6G. At an initial Morphine concentration of 100 ng/ml, the unbound renal clearance to glomerular filtration rate ratio (CLur/GFR) was 5.5 +/- 3.2 (mean +/- SD), indicating that net tubular secretion of Morphine occurred. In the presence of M3G (2000 ng/ml) and M6G (500 ng/ml) this Clur/GFR ratio was elevated to 17.3 +/- 4.8 (p less than .001), which implicates an interaction between these compounds at an active reabsorption transport system. The CLur/GFR ratio for M3G at 2000 ng/ml was 0.90 +/- 0.04, indicating the possibility of a small component of tubular reabsorption, and this ratio was not significantly altered in the presence of Morphine and M6G. M6G was reabsorbed, probably actively, to a greater extent than M3G, with an initial CLur/GFR ratio of 0.67 +/- 0.04, which was not affected when Morphine and M3G were coadministered. These data demonstrate an unusual phenomenon in that the Glucuronide metabolites, which are larger and less lipophilic than the parent drug Morphine, undergo net tubular reabsorption. The renal handling of Morphine is a complex combination of glomerular filtration, active tubular secretion, and possibly active reabsorption.
Margareta Hammarlund-udenaes - One of the best experts on this subject based on the ideXlab platform.
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The influence of age on the distribution of Morphine and Morphine-3-Glucuronide across the blood-brain barrier in sheep.
British Journal of Pharmacology, 2009Co-Authors: J. Bengtsson, Per Ederoth, Karel Marsal, Lena Hellström-westas, Stefan R Hansson, Carl-henrik Nordström, Isis Amer-wåhlin, Margareta Hammarlund-udenaesAbstract:Background and purpose The effect of age on the distribution of Morphine and Morphine-3-Glucuronide (M3G) across the blood-brain barrier (BBB) was studied in a sheep model utilizing intracerebral ...
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The influence of age on the distribution of Morphine and Morphine-3-Glucuronide across the blood-brain barrier in sheep.
British journal of pharmacology, 2009Co-Authors: J. Bengtsson, Per Ederoth, Karel Marsal, Lena Hellström-westas, Stefan R Hansson, Carl-henrik Nordström, Isis Amer-wåhlin, David Ley, Margareta Hammarlund-udenaesAbstract:The effect of age on the distribution of Morphine and Morphine-3-Glucuronide (M3G) across the blood-brain barrier (BBB) was studied in a sheep model utilizing intracerebral microdialysis. The effect of neonatal asphyxia on brain drug distribution was also studied. Microdialysis probes were inserted into the cortex, striatum and blood of 11 lambs (127 gestation days) and six ewes. Morphine, 1 mg x kg(-1), was intravenously administered as a 10 min constant infusion. Microdialysis and blood samples were collected for up to 360 min and analysed using liquid chromatography-tandem mass spectrometry. The half-life, clearance, volume of distribution, unbound drug brain : blood distribution ratio (K(p,uu)) and unbound drug volume of distribution in brain (V(u,brain)) were estimated. Morphine K(p,uu) was 1.19 and 1.89 for the sheep and premature lambs, respectively, indicating that active influx into the brain decreases with age. Induced asphyxia did not affect transport of Morphine or M3G across the BBB. Morphine V(u,brain) measurements were higher in sheep than in premature lambs. The M3G K(p,uu) values were 0.27 and 0.17 in sheep and premature lambs, indicating a net efflux from the brain in both groups. The Morphine K(p,uu) was above unity, indicating active transport into the brain; influx was significantly higher in premature lambs than in adult sheep. These results in sheep differ from those in humans, rats, mice and pigs where a net efflux of Morphine from the brain is observed.
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On-line desalting and determination of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in microdialysis and plasma samples using column switching and liquid chromatography/tandem mass spectrometry.
Rapid communications in mass spectrometry : RCM, 2005Co-Authors: Jörgen Bengtsson, Britt Jansson, Margareta Hammarlund-udenaesAbstract:A sensitive and reproducible method for the determination of Morphine and the metabolites Morphine-3-Glucuronide (M3G) and Morphine-6-Glucuronide (M6G) was developed. The method was validated for perfusion fluid used in microdialysis as well as for sheep and human plasma. A C18 guard column was used to desalt the samples before analytical separation on a ZIC HILIC (hydrophilic interaction chromatography) column and detection with tandem mass spectrometry (MS/MS). The mobile phases were 0.05% trifluoroacetic acid (TFA) for desalting and acetonitrile/5 mM ammonium acetate (70:30) for separation. Microdialysis samples (5 microL) were directly injected onto the system. The lower limits of quantification (LLOQ) for Morphine, M3G and M6G were 0.50, 0.22 and 0.55 ng/mL, respectively, and the method was linear from LLOQ to 200 ng/mL. For plasma, a volume of 100 microL was precipitated with acetonitrile containing internal standards (deuterated Morphine and metabolites). The supernatant was evaporated and reconstituted in 0.05% TFA before the desalting process. The LLOQs for sheep plasma were 2.0 and 3.1 ng/mL and the ranges were 2.0-2000 and 3.1-3100 ng/mL for Morphine and M3G, respectively. For human plasma, the LLOQs were 0.78, 1.49 and 0.53 ng/mL and the ranges were 0.78-500, 1.49-1000 and 0.53-500 ng/mL for Morphine, M3G and M6G, respectively.
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Modelling of the blood-brain barrier transport of Morphine-3-Glucuronide studied using microdialysis in the rat: involvement of probenecid-sensitive transport.
British journal of pharmacology, 2000Co-Authors: Rujia Xie, M. René Bouw, Margareta Hammarlund-udenaesAbstract:The objective of this study was to investigate the impact of probenecid on the blood-brain barrier (BBB) transport of Morphine-3-Glucuronide (M3G). Two groups of rats received an exponential infusion of M3G over 4 h to reach a target plasma concentration of 65 microM on two consecutive days. Probenecid was co-administered in the treatment group on day 2. Microdialysis was used to estimate unbound M3G concentrations in brain extracellular fluid (ECF) and blood. In vivo recovery of M3G was calculated with retrodialysis by drug, preceding the drug administration. The BBB transport was modelled using NONMEM. In the probenecid group, the ratio of the steady-state concentration of unbound M3G in brain ECF to that in blood was 0.08+/-0.02 in the absence and 0.16+/-0.05 in the presence of probenecid (P=0.001). In the control group, no significant difference was found in this ratio between the 2 days (0.11+/-0.05 and 0.10+/-0.02, respectively). The process that appears to be mainly influenced by probenecid is influx clearance into the brain (0.11 microl min(-1) g-brain(-1) vs 0.17 microl min(-1) g-brain(-1), in the absence vs presence of probenecid, P:
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Morphine-3-Glucuronide Has a Minor Effect on Morphine Antinociception. Pharmacodynamic Modeling
Journal of pharmaceutical sciences, 1998Co-Authors: Marie Gårdmark, Mats O. Karlsson, Fredrik U. Jönsson, Margareta Hammarlund-udenaesAbstract:The objective of this study was to quantify the influence of Morphine-3-Glucuronide (M3G) on the Morphine antinociceptive effect (ANE) and respiratory effects in the rat. Three groups of rats were pretreated with either saline or M3G at two different rates. Morphine infusion of 10 mg/h/kg (group A) or 20 mg/h/kg (group B) was administered to each pretreatment group for 3 h. The ANE was measured by the electrical stimulation vocalization method, and blood gas parameters (pCO2, pO2, and pH) were assessed. Independent of pretreatment all groups displayed a concurrent increase in the ANE. The maximal effect diverged between pretreatments. Acute tolerance was observed, but no rebound effect was detected. To characterize the ANE, an effect compartment model and an indirect response model were selected, both capable of describing the observed features. In both models incorporation of M3G led to a better explanation of the data. On the basis of the parameters obtained in the fits, naturally occurring M3G would reduce the antinociceptive effect during a Morphine infusion (plasma concentration 15 microM) by 15-20%. The exposure of M3G did not significantly change the respiratory response following the Morphine treatment.
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Comparison of the disposition of hepatically-generated Morphine-3-Glucuronide and Morphine-6-Glucuronide in isolated perfused liver from the guinea pig.
Pharmaceutical Research, 1997Co-Authors: Robert W. Milne, Rikke Holm Jensen, Allan M. Evans, Claus Larsen, Roger L NationAbstract:Purpose. Humans and guinea pigs metabolise Morphine extensively, forming the isomers Morphine-3-Glucuronide (M3G) and Morphine-6-Glucuronide (M6G) in relatively similar ratios. Both metabolites are formed in the liver, and their greater polarity relative to the parent aglycone may limit their permeability across hepatic membranes. This study compared the disposition of hepatically-generated M3G and M6G in perfused livers isolated from guinea pigs.
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Influence of Renal Failure on the Disposition of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Sheep during Intravenous Infusion with Morphine
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Robert W. Milne, C F Mclean, A J Rutten, L.e. Mather, Roger L Nation, William B. Runciman, Andrew A. SomogyiAbstract:The influence of experimentally induced renal failure on the disposition of Morphine, Morphine-3-Glucuronide (M3G) and Morphine-6-Glucuronide (M6G) was examined in seven sheep infused intravenously with Morphine for 6 hr. Between 5 and 6 hr, blood was collected from the aorta, pulmonary artery, hepatic, hepatic portal and renal veins and posterior vena cava. Additional samples from the aorta and urine were collected up to 144 hr. Morphine, M3G and M6G were determined in plasma and urine by high-performance liquid chromatography. Constant concentrations of Morphine, but not of M3G and M6G, were achieved in plasma between 5 and 6 hr. Significant (P < .001) extraction of Morphine by the liver (0.72 ± 0.05) and kidney (0.42 ± 0.15) occurred. Compared with sheep with normal kidneys ([Milne et al. , 1995][1]), renal failure did not alter (P = .11) the mean total clearance of Morphine (1.5 ± 0.3 liters/min); clearance by the kidney was less (P < .001). However, a paired comparison using sheep common to this study and from the study when their kidneys were normal revealed a significant reduction in mean total clearance of 25%. The renal extraction of M3G and M6G and urinary recovery of the dose as summed Morphine, M3G and M6G were reduced by renal failure. The kidney metabolized Morphine to M3G. The data suggest that nonrenal elimination of M3G becomes more important during renal failure. [1]: #ref-9
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Comparison of the Disposition of Hepatically-Generated Morphine-3-Glucuronide and Morphine-6-Glucuronide in Isolated Perfused Liver from the Guinea Pig
Pharmaceutical research, 1997Co-Authors: Robert W. Milne, Rikke Holm Jensen, Allan M. Evans, Claus Larsen, Roger L NationAbstract:Humans and guinea pigs metabolise Morphine extensively, forming the isomers Morphine-3-Glucuronide (M3G) and Morphine-6-Glucuronide (M6G) in relatively similar ratios. Both metabolites are formed in the liver, and their greater polarity relative to the parent aglycone may limit their permeability across hepatic membranes. This study compared the disposition of hepatically-generated M3G and M6G in perfused livers isolated from guinea pigs. Livers were perfused at 30 ml/min in a non-recirculating manner with Krebs bicarbonate buffer containing Morphine (6 to 7 microM). Perfusing medium, venous perfusate and bile were collected at regular intervals and concentrations of Morphine, M3G and M6G determined by reversed-phase HPLC. Concentrations of Morphine, M3G and M6G in perfusate and the rates of biliary excretion of M3G and M6G were consistent between 20 and 50 min of perfusion. The mean (+/-s.d.) ratio for the rate of formation of M3G relative to M6G was 3.7 +/- 1.5. A mean 33 +/- 3% of Morphine extracted by the liver was recovered as summed M3G and M6G. Of the M3G and M6G formed during a single passage, 19 +/- 11% and 9 +/- 9%, respectively, was excreted into bile; the values were significantly different (P = 0.002). A greater fraction of hepatically-generated M3G excreted into bile compared to that for M6G reflects differences in their relative transport across sinusoidal and canalicular membranes of hepatocytes, possibly via carrier-mediated systems.
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Influence of Renal Failure on the Disposition of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Sheep during Intravenous Infusion with Morphine
The Journal of pharmacology and experimental therapeutics, 1997Co-Authors: Robert W. Milne, C F Mclean, A J Rutten, Roger L Nation, William B. Runciman, Laurence E. Mather, Andrew A. SomogyiAbstract:The influence of experimentally induced renal failure on the disposition of Morphine, Morphine-3-Glucuronide (M3G) and Morphine-6-Glucuronide (M6G) was examined in seven sheep infused intravenously with Morphine for 6 hr. Between 5 and 6 hr, blood was collected from the aorta, pulmonary artery, hepatic, hepatic portal and renal veins and posterior vena cava. Additional samples from the aorta and urine were collected up to 144 hr. Morphine, M3G and M6G were determined in plasma and urine by high-performance liquid chromatography. Constant concentrations of Morphine, but not of M3G and M6G, were achieved in plasma between 5 and 6 hr. Significant (P < .001) extraction of Morphine by the liver (0.72 +/- 0.05) and kidney (0.42 +/- 0.15) occurred. Compared with sheep with normal kidneys (Milne et al., 1995), renal failure did not alter (P = .11) the mean total clearance of Morphine (1.5 +/- 0.3 liters/min); clearance by the kidney was less (P < .001). However, a paired comparison using sheep common to this study and from the study when their kidneys were normal revealed a significant reduction in mean total clearance of 25%. The renal extraction of M3G and M6G and urinary recovery of the dose as summed Morphine, M3G and M6G were reduced by renal failure. The kidney metabolized Morphine to M3G. The data suggest that nonrenal elimination of M3G becomes more important during renal failure.
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Comparative disposition of Morphine-3-Glucuronide during separate intravenous infusions of Morphine and Morphine-3-Glucuronide in sheep. Importance of the kidney.
Drug Metabolism and Disposition, 1995Co-Authors: Robert W. Milne, C F Mclean, A J Rutten, L.e. Mather, Roger L Nation, William B. Runciman, Andrew A. SomogyiAbstract:The disposition of Morphine-3-Glucuronide (M3G) in sheep was compared during separate constant infusions of Morphine and M3G. Five ewes received a 15-min loading dose, followed by a constant infusion of Morphine sulfate (10 mg/hr) or M3G (4 mg/hr for 4 sheep, 7.5 mg/hr for 1 sheep) for a further 5.75 hr. During the 5th-6th hr of infusion, blood was collected simultaneously from the aorta, pulmonary artery, hepatic vein, hepatic portal vein, renal vein, and posterior vena cava. Additional samples were collected from the aorta from 0 to 5 hr and from 6 to 48 hr. Urine was collected via an indwelling catheter from 0 to 6 hr, with further free-flowing urine up to 48 hr. An HPLC assay was used to determine simultaneously Morphine, M3G, and Morphine-6-Glucuronide (M6G) in plasma and urine. Constant concentrations of Morphine, M3G, and M6G in plasma were achieved during the 5- to 6-hr period of infusion with Morphine, as were the concentrations of M3G while M3G was infused. Regional net extraction ratios and total and regional clearances were calculated during the 5- to 6-hr period. After the infusions were ceased, there was prolonged elimination of M3G formed in situ from Morphine compared to when infused as M3G. No Morphine or M6G was detected in the plasma during and after infusion with M3G, nor were they found in urine collected up to 6 hr.(ABSTRACT TRUNCATED AT 250 WORDS)