| 1. |
- Boström, Emma, et al.
(author)
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The Use of Liquid Chromatography/Mass Spectrometry for Quantitative Analysis of Oxycodone, Oxymorphone and Noroxycodone in Ringer Solution, Rat Plasma and Rat Brain Tissue
- 2004
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In: Rapid Communications in Mass Spectrometry. - : Wiley. - 0951-4198 .- 1097-0231. ; 18:21, s. 2565-2576
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Journal article (peer-reviewed)abstract
- Sensitive and reproducible methods for the determination of oxycodone, oxymorphone and noroxycodone in Ringer solution, rat plasma and rat brain tissue by liquid chromatography/mass spectrometry are described. Deuterated analogs of the substances were used as internal standards. Samples in Ringer solution were analyzed by direct injection of 10 microL Ringer solution diluted by an equal volume of water. The limit of quantification was 0.5 ng/mL and the method was linear in the range of 0.5-150 ng/mL for all substances. To analyze oxycodone and oxymorphone in rat plasma, 50 microL of plasma were precipitated with acetonitrile, and the supernatant was directly injected onto the column. To analyze oxycodone, oxymorphone and noroxycodone in rat plasma, 100 microL of rat plasma were subjected to a C18 solid-phase extraction (SPE) procedure, before reconstituting in mobile phase and injection onto the column. For both methods the limit of quantification in rat plasma was 0.5 ng/mL and the methods were linear in the range of 0.5-250 ng/mL for all substances. To analyze the content of oxycodone, oxymorphone and noroxycodone in rat brain tissue, 100 microL of the brain homogenate supernatant were subjected to a C18 SPE procedure. The limit of quantification of oxycodone was 20 ng/g brain, and for oxymorphone and noroxycodone 4 ng/g brain, and the method was linear in the range of 20-1000 ng/g brain for oxycodone and 4-1000 ng/g brain for oxymorphone and noroxycodone. All methods utilized a mobile phase of 5 mM ammonium acetate in 45% acetonitrile, and a SB-CN column was used for separation. The total run time of all methods was 9 min. The intra-day precision and accuracy were <11.3% and <+/-14.9%, respectively, and the inter-day precision and accuracy were <14.9% and <+/-6.5%, respectively, for all the concentrations and matrices described.
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| 2. |
- Bouw, M. René, et al.
(author)
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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
- 2001
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In: British Journal of Pharmacology. - : The British Pharmacological Society. - 0007-1188 .- 1476-5381. ; 134:8, s. 1796-1804
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Journal article (peer-reviewed)abstract
- 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.
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| 3. |
- Ederoth, Per, et al.
(author)
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Blood-brain barrier transport of morphine in patients with severe brain trauma
- 2004
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In: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 57:4, s. 427-435
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Journal article (peer-reviewed)abstract
- AIMS: In experimental studies, morphine pharmacokinetics is different in the brain compared with other tissues due to the properties of the blood-brain barrier, including action of efflux pumps. It was hypothesized in this clinical study that active efflux of morphine occurs also in human brain, and that brain injury would alter cerebral morphine pharmacokinetics. METHODS: Patients with traumatic brain injury, equipped with one to three microdialysis catheters in the brain and one in abdominal subcutaneous fat for metabolic monitoring, were studied. The cerebral catheter locations were classified as 'better' and 'worse' brain tissue, referring to the degree of injury. Morphine (10 mg) was infused intravenously over a 10-min period in seven patients in the intensive care setting. Tissue and plasma morphine concentrations were obtained during the subsequent 3-h period with microdialysis and regular blood sampling. RESULTS: The area under the concentration-time curve (AUC) ratio of unbound morphine in brain tissue to plasma was 0.64 (95% confidence interval 0.40, 0.87) in 'better' brain tissue (P < 0.05 vs. the subcutaneous fat/plasma ratio), 0.78 (0.49, 1.07) in 'worse' brain tissue and 1.00 (0.86, 1.13) in subcutaneous fat. The terminal half-life and T(max) were longer in the brain vs. plasma and fat, respectively. The relative recovery for morphine was higher in 'better' than in 'worse' brain tissue. The T(max) value tended to be shorter in 'worse' brain tissue. CONCLUSIONS: The unbound AUC ratio below unity in the 'better' human brain tissue demonstrates an active efflux of morphine across the blood-brain barrier. The 'worse' brain tissue shows a decrease in relative recovery for morphine and in some cases also an increase in permeability for morphine over the blood-brain barrier.
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| 4. |
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| 5. |
- Tunblad, K, et al.
(author)
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Altered brain exposure of morphine in experimental meningitis studied with microdialysis
- 2004
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In: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 48:3, s. 294-301
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Journal article (peer-reviewed)abstract
- Background: During pathologic conditions such as meningitis and traumatic brain injury the function of the blood-brain barrier (BBB) is disturbed. In the present study we examined the cerebral pharmacokinetic pattern of morphine in the intact brain and during experimentally induced meningitis using a pig model. Secondly, the use of intracerebral microdialysis as a potential tool for monitoring damage in the BBB by studying the pharmacokinetics of morphine is addressed. Methods: Six pigs were studied under general anaesthesia. One occipital and two frontal microdialysis probes and one pressure transducer were inserted into the brain tissue. Another probe was placed into the jugularis interna. Morphine 1 mg kg(-1) was administered as a 10-min infusion, and morphine concentrations were then measured for 3 h. Meningitis was subsequently induced by injecting lipopolysaccharide into the cisterna magna. When meningitis was established, the morphine experiment was repeated. Results: The unbound area under the concentration-time curve (AUC(u)) ratio of morphine in brain to blood was 0.47 (0.19) during the control period, and 0.95 (0.20) (P<0.001) during meningitis. The increase in the brain/blood AUC(u) ratio during meningitis implies decreased active efflux and increased passive diffusion of morphine over the BBB. The half-life of morphine in brain was longer than in blood during both periods, and was unaffected by meningitis. Conclusion: This study demonstrates that the morphine exposure to the brain is significantly increased during meningitis as compared with the control situation.
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| 6. |
- Tunblad, Karin, et al.
(author)
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An integrated model for the analysis of pharmacokinetic data from microdialysis experiments
- 2004
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In: Pharmaceutical research. - 0724-8741 .- 1573-904X. ; 21:9, s. 1698-1707
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Journal article (peer-reviewed)abstract
- PURPOSE: To develop an integrated model for microdialysis data that incorporates all data including the recovery measurements in one model, and to compare this model to a previous model and the results from a noncompartmental analysis. METHODS: The models were developed in NONMEM. The modes of analysis were compared with respect to parameter estimates, model structures, gained mechanistic insight, and practical aspects. RESULTS: Both modeling approaches resulted in similar model structures. The parameter estimates in blood and brain from the models and the results from the noncompartmental analysis were comparable. Using the integrated model all data, that is, the total arterial concentrations, the venous and brain dialysate concentrations, and the recovery measurements, were analyzed simultaneously. CONCLUSION: The theoretical benefits of the integrated model are related to the inclusion of the recovery in the model and the use of all collected data as it was observed. Thus, all data are described in a single model, corrections for the recovery and the protein binding are done within the model, and the dialysate observations are described by the integral over each collection interval. Thereby, the variability and the uncertainty in the model parameters are handled correctly to give more reliable parameter estimates.
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| 7. |
- Tunblad, Karin, 1973-
(author)
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Blood-Brain Barrier Transport of Drugs Across Species with the Emphasis on Health, Disease and Modelling
- 2004
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Doctoral thesis (other academic/artistic)abstract
- The transport of drugs across the blood-brain barrier (BBB) has been investigated in different species using morphine and morphine-6-glucuronide (M6G) as model compounds. The influence of probenecid on the BBB transport of morphine and M6G was investigated, and the consequences of meningitis and severe brain injury on the concentrations of morphine in the brain were examined. All data were obtained by microdialysis, and data analysis using mathematical models was emphasised.Morphine is exposed to active efflux at the BBB in rats, pigs and humans. In addition, the half-life of morphine is longer in the brain than in blood in these species. These interspecies similarities show the predictive potential of the two animal models for the BBB transport of morphine in humans. In the pig the exposure of the brain to morphine was higher in the presence of meningitis than when healthy. This was interpreted as a decrease in the active efflux and an increase in the passive diffusion over the injured BBB. In contrast, there was no significant difference in the concentrations of morphine in the “better” (uninjured) or the “worse” (injured) brain tissue in brain trauma patients. The extent of the transport across the BBB is similar for morphine and M6G. However, co-administration of probenecid only increased the brain concentrations of morphine, demonstrating that morphine and M6G are substrates for different efflux transporters at the BBB. An integrated model for the analysis of data obtained by microdialysis was developed. This model makes fewer assumptions about the recovery, the protein binding and the time of the dialysate observation than a previous model and traditional non-compartmental analysis and should, therefore, yield more reliable parameter estimates.Knowledge of the consequences of efflux transporters and disease on the brain concentrations of a drug can be useful for individualising the dosing regimen in patients.
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| 8. |
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| 9. |
- Tunblad, Karin, et al.
(author)
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Morphine blood-brain barrier transport is influenced by probenecid co-administration
- 2003
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In: Pharmaceutical research. - 0724-8741 .- 1573-904X. ; 20:4, s. 618-623
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Journal article (peer-reviewed)abstract
- PURPOSE: The objective of this study was to investigate the possible influence of probenecid on morphine transport across the blood-brain barrier (BBB) in rats. METHODS: Microdialysis probes, calibrated using retrodialysis by drug, were placed into the striatum and jugular vein of seven Sprague-Dawley rats. Morphine was administered as a 4-h exponential infusion. The experiment was repeated the next day with the addition of probenecid, administered as a bolus dose (20 mg/kg) followed by a constant infusion (20 mg/kg/h). Models for BBB transport were built using the computer program NONMEM. RESULTS: The steady-state ratio of 0.29 +/- 0.07 of unbound morphine concentration in brain to that in blood indicates that morphine is actively effluxed at the BBB. Probenecid co-administration increased the ratio to 0.39 +/- 0.04 (p < 0.05). Models in which probenecid influenced the brain efflux clearance rather than the influx clearance, well described the data. The half-life in brain increased from 58 +/- 9 min to 115 +/- 25 min when probenecid was co-administered. Systemic clearance of morphine also decreased upon probenecid co-administration, and M3G formation was decreased. CONCLUSION: This study indicates that morphine is a substrate for the probenecid-sensitive transporters at the BBB. Co-administration of probenecid decreased the brain efflux clearance of morphine.
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