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The Journal of Pharmacy and Pharmacology Feb 1995The pharmacokinetics of morphine in plasma and the distribution of morphine and its glucuronidated metabolites within the cerebrospinal fluid were investigated in... (Comparative Study)
Comparative Study
The pharmacokinetics of morphine in plasma and the distribution of morphine and its glucuronidated metabolites within the cerebrospinal fluid were investigated in rabbits. After single morphine dosage, the plasma AUC ratio of morphine-3- glucuronide/morphine was 11.1 compared with 0.14 for morphine-6-glucuronide/morphine. The similar elimination half-lives of morphine (107 min), morphine-3-glucuronide (122 min), and morphine-6-glucuronide (105 min) suggested the glucuronidation to be the rate-limiting step, which was substantiated by the observation that morphine-3-glucuronide becomes eliminated four times faster when applied intravenously. Both after single and repeated morphine administration, the ratios of CSF and plasma levels of the parent drug were higher than those of morphine-3-glucuronide or morphine-6-glucuronide. These data demonstrate a poor penetration of the glucuronides across the blood-brain barrier and do not support the previously postulated accumulation of morphine-6-glucuronide in the central nervous system during chronic morphine treatment.
Topics: Animals; Blood-Brain Barrier; Central Nervous System; Chromatography, High Pressure Liquid; Half-Life; Injections, Subcutaneous; Male; Morphine; Morphine Derivatives; Rabbits
PubMed: 7602474
DOI: 10.1111/j.2042-7158.1995.tb05772.x -
Therapeutic Drug Monitoring Apr 1994An original, sensitive, and specific high-performance liquid chromatographic (HPLC) assay was developed for the quantitation of morphine and its two major metabolites,...
Quantitation of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in plasma and cerebrospinal fluid using solid-phase extraction and high-performance liquid chromatography with electrochemical detection.
An original, sensitive, and specific high-performance liquid chromatographic (HPLC) assay was developed for the quantitation of morphine and its two major metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), in human plasma and cerebrospinal fluid (CSF) and in rat plasma, using hydromorphone as the internal standard. Solid-phase extraction was used to separate morphine and its glucuronide metabolites from plasma constituents. Extraction efficiencies of morphine, M3G, and M6G from human plasma samples (0.5 ml) were 84, 87, and 88%, respectively. Extraction efficiencies of morphine, M3G, and M6G did not differ significantly (p > 0.05) between human plasma and CSF or rat plasma. Morphine, M3G, M6G, and hydromorphone were separated on a 10 mu C8 Resolve radially compressed cartridge using a mobile phase comprising methanol:acetonitrile:phosphate buffer, (0.0125M pH 7.5; 10:10:80), in which 11 mg/L of cetyltrimethylammonium bromide (cetrimide) was dissolved. Quantitation was achieved using a single electrochemical detector at ambient temperature (23 degrees C). Standard curves were linear over the ranges 0.020-2.190, 0.027-2.709, and 0.027-0.542 microM for morphine, M3G, and M6G, respectively. Lower limits of detection for morphine, M3G, and M6G in human plasma and CSF samples (0.5 ml) were 0.020, 0.027, and 0.027 microM, respectively. Corresponding lower limits of detection in rat plasma (0.1 ml) were 0.102, 0.135, and 0.135 microM, respectively. Intraassay precision for low and high concentrations of morphine, M3G, and M6G were < 23 and < 8% respectively. Similarly, interassay accuracy for low and medium concentrations of morphine, M3G, and M6G were < 17% and were < 9% for high concentrations.
Topics: Animals; Chromatography, High Pressure Liquid; Electrochemistry; Humans; Morphine; Morphine Derivatives; Rats; Reproducibility of Results; Sensitivity and Specificity
PubMed: 8009570
DOI: 10.1097/00007691-199404000-00016 -
Journal of Veterinary Pharmacology and... Aug 2014The objective of the current study was to describe the pharmacokinetics of morphine and its metabolites following intravenous administration to the horse. A total of...
The objective of the current study was to describe the pharmacokinetics of morphine and its metabolites following intravenous administration to the horse. A total of eight horses (two per dose group) received a single intravenous dose of 0.05, 0.1, 0.2, or 0.5 mg/kg morphine. Blood samples were collected up to 72 h postdrug administration, analyzed using LC-MS/MS and pharmacokinetic parameters determined. Behavior, step counts, and gastrointestinal activity were also assessed. The beta and gamma half-life for morphine ranged from 0.675 to 2.09 and 6.70 to 18.1 h, respectively, following administration of the four different IV doses. The volume of distribution at steady-state and systemic clearance ranged from 6.95 to 15.8 L/kg and 28.3 to 35.7 mL · min/kg, respectively. The only metabolites identified in blood samples were the primary metabolites identified in other species, 3-morphine-glucuronide and 6-morphine-glucuronide. Muscle fasciculations were observed at 0.2 and 0.5 mg/kg and ataxia noted at 0.5 mg/kg. Gastrointestinal activity was decreased in all dose groups (for up to 8 h in 7/8 horses and 24 h in one horse). This study extends previous studies and is the first report describing the metabolites of morphine in the horse. Plasma concentrations of morphine-3-glucuronide, a metabolite with demonstrated neuro-excitatory activity in mice, far exceeded that of morphine-6-glucuronide. Further study is warranted to assess whether the high levels of the morphine-3-glucuronide contribute to the dose-dependent excitation observed at high morphine doses.
Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Female; Horses; Injections, Intravenous; Male; Morphine; Morphine Derivatives
PubMed: 24479785
DOI: 10.1111/jvp.12098 -
Journal of Pharmaceutical and... Sep 2001A reversed-phase high-performance liquid chromatographic method with coulometric and UV detection has been developed for the simultaneous determination of morphine,...
A reversed-phase high-performance liquid chromatographic method with coulometric and UV detection has been developed for the simultaneous determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide. The separation was carried out by using a Supelcosil LC-8 DB reversed-phase column and 0.1 M potassium dihydrogen phosphate (pH 2.5)--acetonitrile--methanol (94:5:1 v/v) containing 4 mM pentanesulfonic acid as the mobile phase. The compounds were determined simultaneously by coulometry for morphine and with UV detection for morphine-3-glucuronide and morphine-6-glucuronide. Morphine, morphine glucuronides and the internal standard were extracted from human plasma using Bond-Elut C18 (1 ml) solid-phase extraction cartridges. In the case of coulometric detection, the detection limit was 0.5 ng/ml for morphine; in the case of UV detection the detection limit was 10 ng/ml for morphine-3-glucuronide and for morphine-6-glucuronide, too.
Topics: Chromatography, High Pressure Liquid; Colorimetry; Humans; Morphine; Morphine Derivatives; Spectrophotometry, Ultraviolet; Therapeutic Equivalency
PubMed: 11470195
DOI: 10.1016/s0731-7085(01)00393-4 -
Therapeutic Drug Monitoring Jun 1995Healthy volunteers were given morphine as an i.v. infusion (10 mg), immediate release (IR) tablets (3 x 10 mg), and as a new controlled release (CR) tablet (30 mg) on...
Plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide after intravenous and oral administration to healthy volunteers: relationship to nonanalgesic actions.
Healthy volunteers were given morphine as an i.v. infusion (10 mg), immediate release (IR) tablets (3 x 10 mg), and as a new controlled release (CR) tablet (30 mg) on separate occasions. Venous blood samples were analyzed for morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) using high-performance liquid chromatography (HPLC). Pupil size, salivation, and central nervous system (CNS) effects were evaluated serially. Pharmacokinetic parameters, calculated using a two-compartment model, were in accordance with previous results for i.v. administration of morphine. The absolute bioavailability of morphine in both IR and in CR tablets was, 32%, and the relative bioavailability of the CR tablet versus the IR tablets was 103% (91-115%, 95% confidence interval). Pupil size and unstimulated saliva production were significantly reduced and CNS effects most pronounced following i.v. infusion of morphine, but were only moderately affected after oral administration with IR or CR tablets. Miosis and reduction of salivation were observed at moderate concentrations of morphine and M6G. A pharmacokinetic/pharmacodynamic model based on previous studies of receptor binding and potency of morphine and its metabolites was used to assess the concentration-effect relationships. According to this model, M6G was four and eight times more potent than morphine in producing miosis and reduction of saliva production, respectively. The same model indicated that intrinsic activities of M6G and morphine were similar for both effect parameters, whereas M3G was either inactive or even opposed the effects of morphine and M6G.
Topics: Administration, Oral; Adult; Biological Availability; Brain; Female; Humans; Injections, Intravenous; Male; Miosis; Morphine; Morphine Derivatives; Salivation
PubMed: 7624926
DOI: 10.1097/00007691-199506000-00013 -
The Journal of Pharmacology and... Nov 1989Morphine-6 beta-glucuronide is a major metabolite of morphine with potent analgesic actions. To define more fully the importance of this compound in morphine action, we...
Morphine-6 beta-glucuronide is a major metabolite of morphine with potent analgesic actions. To define more fully the importance of this compound in morphine action, we have compared the analgesic actions of morphine and its 6 beta-glucuronide metabolite after both peripheral and central administration. Given s.c., morphine-6 beta-glucuronide elicited analgesia with an effect approximately twice that of morphine due, in part, to its long duration of action and also inhibited gastrointestinal motility. Both actions were easily reversed by naloxone (s.c.). However, when injected either i.c.v. or intrathecally, morphine-6 beta-glucuronide was approximately 90- and 650-fold more potent an analgesic than morphine, respectively. Whereas morphine in these studies was equipotent at both levels of the neuraxis as an analgesic, the 6 beta-glucuronide was approximately 5-fold more effective at the level of the spinal cord than supraspinally. The mu 1-selective antagonist naloxonazine blocked the analgesic effect of systemic and i.c.v. morphine-6 beta-glucuronide much as it blocked morphine, implying a role for mu1 receptors in these actions. Like morphine, morphine-6 beta-glucuronide analgesia after intrathecal injection was not sensitive to naloxonazine, suggesting a mu2 mechanism within the spinal cord. Together, these results imply that morphine-6 beta-glucuronide elicited its analgesic actions through the same receptor mechanisms as morphine. Mice highly tolerant to morphine after implantation of morphine pellets showed cross-tolerance to morphine-6 beta-glucuronide (s.c.). The high potency of morphine-6 beta-glucuronide strongly suggests that this metabolite plays an important role in morphine's actions.
Topics: Analgesia; Animals; Drug Tolerance; Gastrointestinal Motility; Male; Mice; Morphine; Morphine Derivatives; Naloxone
PubMed: 2810109
DOI: No ID Found -
Brain Research. Molecular Brain Research Mar 2001Morphine and morphine-6-glucuronide, a morphine metabolite, have been identified and quantified in Mytilus edulis pedal ganglia at a level of 2.67+/-0.44 and 0.98+/-0.14...
Presence of morphine and morphine-6-glucuronide in the marine mollusk Mytilus edulis ganglia determined by GC/MS and Q-TOF-MS. Starvation increases opiate alkaloid levels.
Morphine and morphine-6-glucuronide, a morphine metabolite, have been identified and quantified in Mytilus edulis pedal ganglia at a level of 2.67+/-0.44 and 0.98+/-0.14 ng/ganglia, respectively by high performance liquid chromatography coupled to electrochemical detection. These opiate alkaloids were further identified by both gas-chromatography mass spectrometry and nanoflow electrospray ionization double quadrupole orthogonal acceleration Time of Flight mass spectrometry. In animals that were starved, the morphine level rose to 6.38+/-0.88 ng/ganglion and the morphine 6-glucoronide rose to a level of 23.0+/-3.2 ng/ganglion after 30 days. These studies demonstrate that opiate alkaloids are present as naturally occurring signal molecules whose levels respond to stress, i.e., starvation. Opiate alkaloids were not found in the animal's incubation media or food, demonstrating their synthesis occurred in the respective tissue. These new method of opiate alkaloid detection, conclusively proves that morphine and morphine-6-glucuronide are present in animal tissues.
Topics: Animals; Bivalvia; Chromatography, High Pressure Liquid; Ganglia, Invertebrate; Gas Chromatography-Mass Spectrometry; Morphine; Morphine Derivatives; Starvation
PubMed: 11295241
DOI: 10.1016/s0169-328x(01)00048-1 -
Drug Metabolism and Disposition: the... 1991The isolated perfused rat kidney was used to examine the renal handling of morphine and its inactive metabolite morphine-3-glucuronide (M3G), and active metabolite...
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.
Topics: Animals; Biological Transport; Dose-Response Relationship, Drug; Drug Interactions; Glomerular Filtration Rate; Kidney; Kidney Tubules; Male; Morphine; Morphine Derivatives; Perfusion; Rats; Rats, Inbred Strains
PubMed: 1687015
DOI: No ID Found -
Clinical Chemistry Oct 2022
Topics: Humans; Morphine; Heroin Dependence; Morphine Derivatives; Body Fluids
PubMed: 37619530
DOI: 10.1093/clinchem/hvac110 -
Forensic Science International Jul 2015Heroin is de-acetylated in the body to morphine in two steps. The intermediate 6-acetylmorphine (6-AM) is formed rapidly and is considered important for the...
Heroin is de-acetylated in the body to morphine in two steps. The intermediate 6-acetylmorphine (6-AM) is formed rapidly and is considered important for the pharmacological effect of heroin. In urine drug testing, an atypical pattern of morphine and 6-AM is known to occur in low frequency. The aim of this study was to investigate this atypical pattern in more detail and to identify responsible substances for a possible inhibition of the conversion from 6-AM to morphine. Urine samples were selected from a routine flow of samples sent for drug testing. Out of 695 samples containing morphine and 6-acetylmorphine, 11.5% had the atypical pattern of a 6-AM to morphine ratio above 0.26 as derived from a bimodal frequency distribution. An in vitro study of the conversion of 6-acetylmorphine to morphine in human liver homogenates demonstrated that a number of known carboxylesterase inhibitors were able to inhibit the reaction mimicking the situation in vivo. Compound 3 (3,6-Dimethoxy-4-acetoxy-5-[2-(N-methylacetamido)ethyl]phenanthrene) a substance formed from thebaine during the production of heroin was found to be a strong inhibitor. Liquid chromatography-mass spectrometry was used to identify possible inhibitors present in vivo. This part of the investigation demonstrated that several components may contribute to the effect. It is concluded that inhibition of liver carboxylesterase activity is a possible mechanism causing the atypical pattern and that one candidate compound is the result of the heroin production process. An inhibition of 6-AM metabolism is likely to increase the pharmacological effect of heroin and may be related to a higher risk of lethal toxicity.
Topics: Caffeine; Carboxylesterase; Central Nervous System Depressants; Central Nervous System Stimulants; Chromatography, Liquid; Ethanol; Forensic Toxicology; Heroin Dependence; Humans; Liver; Mass Spectrometry; Morphine; Morphine Derivatives; Narcotics; Salicylic Acid; Thebaine
PubMed: 26002801
DOI: 10.1016/j.forsciint.2015.05.002