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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.

ABSTRACT: 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:<0.001). The efflux clearance was 1.15 microl min(-1) g-brain(-1). The half-life of M3G was 81+/-25 min in brain ECF vs 22+/-2 min in blood (P<0.0001). Blood pharmacokinetics was not influenced by probenecid. In conclusion, a probenecid-sensitive transport system is involved in the transport of M3G across the BBB.

SUBMITTER: Xie R

PROVIDER: S-EPMC1572517 | biostudies-other | 2000 Dec

REPOSITORIES: biostudies-other

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Blood-brain barrier transport and brain distribution of morphine-6-glucuronide in relation to the antinociceptive effect in rats--pharmacokinetic/pharmacodynamic modelling.

Project description:1. The objective of this study was to investigate the contribution of the blood-brain barrier (BBB) transport to the delay in antinociceptive effect of morphine-6-glucuronide (M6G), and to study the equilibration of M6G in vivo across the BBB with microdialysis measuring unbound concentrations. 2. On two consecutive days, rats received an exponential infusion of M6G for 4 h aiming at a target concentration of 3000 ng ml(-1) (6.5 microM) in blood. Concentrations of unbound M6G were determined in brain extracellular fluid (ECF) and venous blood using microdialysis and in arterial blood by regular sampling. MD probes were calibrated in vivo using retrodialysis by drug prior to drug administration. 3. The half-life of M6G was 23+/-5 min in arterial blood, 26+/-10 min in venous blood and 58+/-17 min in brain ECF (P<0.05; brain vs blood). The BBB equilibration, expressed as the unbound steady-state concentration ratio, was 0.22+/-0.09, indicating active efflux in the BBB transport of M6G. A two-compartment model best described the brain distribution of M6G. The unbound volume of distribution was 0.20+/-0.02 ml g brain(-1). The concentration-antinociceptive effect relationships exhibited a clear hysteresis, resulting in an effect delay half-life of 103 min in relation to blood concentrations and a remaining effect delay half-life of 53 min in relation to brain ECF concentrations. 4. Half the effect delay of M6G can be explained by transport across the BBB, suggesting that the remaining effect delay of 53 min is a result of drug distribution within the brain tissue or rate-limiting mechanisms at the receptor level.

| S-EPMC1572896 | biostudies-other

Blood-Placental Barrier Transfers and Pharmacokinetics of Unbound Morphine in Pregnant Rats with Multiple Microdialysis Systems.

Project description:Microdialysis coupled to an analytical system can be used to continuously monitor unbound protein analytes in any biological fluid, tissue, or organ of animals. To date, no application of microdialysis has been performed to simultaneously monitor unbound morphine and its metabolites in the placenta and fetus of pregnant rats. Our hypothesis is that morphine and its metabolite penetrate the blood-placental barrier to reach the fetus during pregnancy. To investigate this hypothesis, this study aimed to develop a microdialysis experimental animal model coupled with an analytical system to monitor morphine and morphine-3-glucuronide (M3G) in the maternal blood, placenta, fetus, and amniotic fluid of pregnant rats. To determine the analytes in dialysates, a validated ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed. The pharmacokinetic results indicated that morphine fit well to a two-compartment model and exhibited nonlinear pharmacokinetic behavior within the dosage regimen. The M3G-to-morphine metabolite ratio, determined by the area under the concentration curve (AUC) ratio (AUCM3G/AUCmorphine), was approximately 5.40 in the maternal blood. In terms of tissue distribution, the mother-to-fetus transfer ratio (AUCfetus/AUCblood) of morphine and M3G was about 0.34 and 0.18, respectively. In conclusion, the high metabolite ratio suggests that morphine has the characteristics of rapid biotransformation, and the mother-to-fetus transfer ratio indicates that morphine and M3G partially transfer the blood-placental barrier in pregnant rats. This newly developed multiple microdialysis coupled to UHPLC-MS/MS system can be applied to the studies of maternal pharmacokinetics and blood-placental transfer in pregnant rats.

| S-EPMC8506599 | biostudies-literature

Influence of Morbid Obesity on the Pharmacokinetics of Morphine, Morphine-3-Glucuronide, and Morphine-6-Glucuronide.

Project description:INTRODUCTION:Obesity is associated with many pathophysiological changes that may result in altered drug metabolism. The aim of this study is to investigate the influence of obesity on the pharmacokinetics of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a combined analysis in morbidly obese patients and non-obese healthy volunteers. METHODS:In this analysis, data from 20 morbidly obese patients [mean body mass index 49.9 kg/m2 (range 37.6-78.6 kg/m2) and weight 151.3 kg (range 112-251.9 kg)] and 20 healthy volunteers [mean weight 70.6 kg (range 58-85 kg)] were included. Morbidly obese patients received 10 mg of intravenous (I.V.) morphine after gastric bypass surgery, with additional morphine I.V. doses as needed. Healthy volunteers received an I.V. bolus of morphine of 0.1 mg/kg followed by an infusion of 0.030 mg kg-1 h-1 for 1 h. Population pharmacokinetic modeling was performed using NONMEM 7.2. RESULTS:In morbidly obese patients, elimination clearance of M3G and M6G was decreased substantially compared with healthy volunteers (p < 0.001). Regarding glucuronidation, only a slight decrease in the formation of M6G and a delay in the formation of M3G was found (both p < 0.001). Obesity was also identified as a covariate for the peripheral volume of distribution of morphine (p < 0.001). CONCLUSION:Metabolism of morphine is not altered in morbidly obese patients. However, decreased elimination of both M3G and M6G is evident, resulting in a substantial increase in exposure to these two metabolites. A rational explanation of this finding is that it results from alterations in membrane transporter function and/or expression in the liver. ClinicalTrials.gov identifier: NCT01097148.

| S-EPMC5694499 | biostudies-literature

Blood-brain distribution of morphine-6-glucuronide in sheep.

Project description:At present there are few data regarding the rate and extent of brain-blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented conscious sheep.Five sheep received an intravenous infusion of M6G 2.2 mg kg(-1) over a four-minute period. Non-linear mixed-effects analysis, with hybrid physiologically based kinetic models, was used to estimate cerebral kinetics from the arterio-sagittal sinus concentration gradients and cerebral blood flow measurements.A membrane limited model was selected as the final model. The blood-brain equilibration of M6G was relatively slow (time to reach 50% equilibration of the deep compartment 5.8 min), with low membrane permeability (PS, population mean, 2.5 ml min(-1)) from the initial compartment (V1, 13.7 ml) to a small deep distribution volume (V2) of 18.4 ml. There was some between-animal variability (%CV) in the initial distribution volume (29%), but this was not identified for PS or V2.Pharmacokinetic modelling of M6G showed a delayed equilibration between brain and blood of a nature that is primarily limited by permeability across the blood-brain-barrier, in accordance with its physico-chemical properties.

| S-EPMC2014650 | biostudies-other

Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide.

Project description:Opiates are potent analgesics but their clinical use is limited by side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). The Opiates produce analgesia and other adverse effects through activation of the mu opioid receptor (MOR) encoded by the Oprm1 gene. However, MOR and morphine metabolism involvement in OIH have been little explored. Hence, we examined MOR contribution to OIH by comparing morphine-induced hyperalgesia in wild type (WT) and MOR knockout (KO) mice. We found that repeated morphine administration led to analgesic tolerance and hyperalgesia in WT mice but not in MOR KO mice. The absence of OIH in MOR KO mice was found in both sexes, in two KO global mutant lines, and for mechanical, heat and cold pain modalities. In addition, the morphine metabolite morphine-3beta-D-glucuronide (M3G) elicited hyperalgesia in WT but not in MOR KO animals, as well as in both MOR flox and MOR-Nav1.8 sensory neuron conditional KO mice. M3G displayed significant binding to MOR and G-protein activation when using membranes from MOR-transfected cells or WT mice but not from MOR KO mice. Collectively our results show that MOR is involved in hyperalgesia induced by chronic morphine and its metabolite M3G.

| S-EPMC5583172 | biostudies-literature

The development of a high-performance liquid chromatography-tandem mass spectrometric method for simultaneous quantification of morphine, morphine-3-?-glucuronide, morphine-6-?-glucuronide, hydromorphone, and normorphine in serum.

Project description:Development and validation of a selective, robust high-performance liquid chromatography-tandem mass spectrometric (HPLC/MS-MS) method for the quantification of morphine, morphine-3-?-glucuronide, morphine-6-?-glucuronide, hydromorphone, and normorphine in human serum.Drug-free human serum samples spiked with morphine, morphine-3-?-glucuronide, morphine-6-?-glucuronide, hydromorphone, and normorphine were prepared by protein precipitation using methanol containing the internal standards. Samples were injected onto a Thermo Scientific AccuCore PFP column for chromatographic separation. Detection was achieved using a Thermo Scientific TSQ Vantage mass spectrometer. Assay validation followed the new Clinical and Laboratory Standards Institute (CLSI) C62-A guidelines.The analytical measuring range for all analytes was determined to be 5 to 1000 ng/mL. Intra- and inter-assay precision for three quality control levels were ? 7.0% and ? 13.5%, respectively. Carryover, stability, linearity, matrix effects, extraction and processing efficiency and method comparison characteristics were acceptable relative to the CLSI C62 guidelines.The validation of this HPLC-MS/MS method demonstrated a robust and rapid assay for the quantification of morphine, morphine-3-?-glucuronide, morphine-6-?-glucuronide, hydromorphone, and normorphine.

| S-EPMC4679425 | biostudies-literature

Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception.

Project description:Glucuronidation is a major detoxification pathway for endogenous and exogenous compounds in mammals that results in the intracellular formation of polar metabolites, requiring specialized transporters to cross biological membranes. By using morphine as a model aglycone, we demonstrate that multidrug resistance protein 3 (MRP3/ABCC3), a protein present in the basolateral membrane of polarized cells, transports morphine-3-glucuronide (M3G) and morphine-6-glucuronide in vitro. Mrp3(-/-) mice are unable to excrete M3G from the liver into the bloodstream, the major hepatic elimination route for this drug. This results in increased levels of M3G in liver and bile, a 50-fold reduction in the plasma levels of M3G, and in a major shift in the main disposition route for morphine and M3G, predominantly via the urine in WT mice but via the feces in Mrp3(-/-) mice. The pharamacokinetics of injected morphine-glucuronides are altered as well in the absence of Mrp3, and this results in a decreased antinociceptive potency of injected morphine-6-glucuronide.

| S-EPMC1091780 | biostudies-literature

Copper transport to the brain by the blood-brain barrier and blood-CSF barrier.

Project description:The mechanism of copper (Cu) transport into the brain is unclear. This study evaluated the main species and route of Cu transport into the brain using in situ brain perfusion technique, and assessed the levels of mRNA encoding Cu transporters using real time RT-PCR. Free (64)Cu uptake in rat choroid plexus (CP), where the blood-cerebrospinal fluid barrier (BCB) is primarily located, is about 50 and 1000 times higher than (64)Cu-albumin and (64)Cu-ceruloplasmin uptake, respectively. The unidirectional transport rate constants (K(in)) for Cu in the CP and brain capillaries of the blood-brain barrier (BBB) were 1034 and 319 microl/s/g, respectively, while K(in) in CSF and capillary-depleted parenchyma were much reduced, 0.8 and 112 microl/s/g, respectively. The K(in) in cerebellum was significantly lower than that in hippocampus. The mRNAs encoding Cu transporter-1 (Ctr1) and ATP7A were higher in the CP than those in brain capillaries and parenchyma, whereas ATP7B mRNA was higher in brain capillaries than those in the CP and brain parenchyma. Taken together, these data suggest that the expression of Cu transporters is higher in brain barriers than in brain parenchyma; the Cu transport into the brain is mainly achieved through the BBB as a free Cu ion and the BCB may serve as a main regulatory site of Cu in the CSF.

| S-EPMC2677986 | biostudies-literature

Simultaneous blood and brain microdialysis in a free-moving mouse to test blood-brain barrier permeability of chemicals.

Project description:Neurotoxic chemicals that pass through the blood-brain barrier (BBB) can influence brain function. Efficient methods to test the permeability of the BBB to specific chemicals would facilitate identification of potentially neurotoxic agents. We report here a simultaneous blood and brain microdialysis in a free-moving mouse to test BBB permeability of different chemicals. Microdialysis sampling was conducted in mice at 3-5 days after implantation of a brain microdialysis probe and 1 day after implantation of a blood microdialysis probe. Therefore, mice were under almost physiological conditions. Results of an intravenous injection of lucifer yellow or uranine showed that the BBB was functioning in the mice under the experimental conditions. Mice were given phenyl arsenic compounds orally, and concentration-time profiles for phenyl arsenic compounds such as diphenylarsinic acid, phenylarsonic acid, and phenylmethylarsinic acid in the blood and brain dialysate samples were obtained using simultaneous blood and brain microdialysis coupled with liquid chromatography-tandem mass spectrometry. Peak area-time profiles for linalool and 2-phenethyl alcohol (fragrance compounds or plant-derived volatile organic chemicals) were obtained using simultaneous blood and brain microdialysis coupled with gas chromatography-mass spectrometry in mice given lavender or rose essential oils intraperitoneally. BBB function was confirmed using lucifer yellow in these mice, and results indicated that the phenyl arsenic compounds, linalool and 2-phenethyl alcohol, passed through the BBB. The present study demonstrates that simultaneous blood and brain microdialysis in a free-moving mouse makes it possible to test the BBB permeability of chemicals when coupled with appropriate chemical analysis methods.

| S-EPMC7689036 | biostudies-literature

Using microdialysis to analyse the passage of monovalent nanobodies through the blood-brain barrier.

Project description:BACKGROUND AND PURPOSE: Nanobodies are promising antigen-binding moieties for molecular imaging and therapeutic purposes because of their favourable pharmacological and pharmacokinetic properties. However, the capability of monovalent nanobodies to reach targets in the CNS remains to be demonstrated. EXPERIMENTAL APPROACH: We have assessed the blood-brain barrier permeability of Nb_An33, a nanobody against the Trypanosoma brucei brucei variant-specific surface glycoprotein (VSG). This analysis was performed in healthy rats and in rats that were in the encephalitic stage of African trypanosomiasis using intracerebral microdialysis, single photon emission computed tomography (SPECT) or a combination of both methodologies. This enabled the quantification of unlabelled and (99m) Tc-labelled nanobodies using, respectively, a sensitive VSG-based nanobody-detection elisa, radioactivity measurement in collected microdialysates and SPECT image analysis. KEY RESULTS: The combined read-out methodologies showed that Nb_An33 was detected in the brain of healthy rats following i.v. injection, inflammation-induced damage to the blood-brain barrier, as in the late encephalitic stage of trypanosomiasis, significantly increased the efficiency of passage of the nanobody through this barrier. Complementing SPECT analyses with intracerebral microdialysis improved analysis of brain disposition. There is clear value in assessing penetration of the blood-brain barrier by monovalent nanobodies in models of CNS inflammation. Our data also suggest that rapid clearance from blood might hamper efficient targeting of specific nanobodies to the CNS. CONCLUSIONS AND IMPLICATIONS: Nanobodies can enter the brain parenchyma from the systemic circulation, especially in pathological conditions where the blood-brain barrier integrity is compromised.

| S-EPMC3413867 | biostudies-other

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