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- Bouw, M. René, et al.
(författare)
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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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Ingår i: British Journal of Pharmacology. - : The British Pharmacological Society. - 0007-1188 .- 1476-5381. ; 134:8, s. 1796-1804
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Bouw, Marcel René
(författare)
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Microdialysis as a tool in pharmacokinetic-pharmacodynamic studies investigating the brain distribution and effect delay of morphine and morphine-6-glucuronide
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The microdialysis technique was developed as a tool for studying the pharmacokinetic and pharmacodynamicrelationships of morphine and morphine-6-glucronide (M6G). Concentrations of unbound drug in blood andbrain were monitored in order to elucidate the origin of the observed delay in antinociceptive effect in rats.The antinociceptive effect was measured as the response to electrical stimulation of the tail and respiratoryeffects were monitored by measuring the blood gas status. The data analysis was performed in NONMEM andPCNONLIN. It was shown that in vitro testing is an essential step in the selection of a candidate drug for in vivomicrodialysis. A comparative study of in vivo calibration methods showed no significant difference betweenthe unbound concentration-time profiles obtained with retrodialysis by drug or by calibrator (nalorphine).The delay in antinociceptive effect of morphine in relation to the blood concentration was estimated to havean equilibration half-life of 32 min, which was considerably shorter than the equilibration half-life of 103 minfor M6G. Remaining effect delays of 5 or 53 mitt, respectively, were observed when the effect was related tothe brain extracellular fluid (ECF) concentrations of morphine and M6G. Unexpectedly, the brain ECF:bloodratio for unbound morphine (0.25 ± 0.13) was comparable with the value for M6G (0,22 ± O.O9), indicating theinvolvement of active mechanisms of transport across the blood-brain barrier (BBB) for both compounds.Significantly longer half-lives for morphine and M6G were observed in brain (43 ± 9 and 58 ± 17 min,respectively) than in blood (31 ± 8 and 23 ± 5 min, respectively), Thus, redistribution in the brain is the ratelimiting step for the elimination of both morphine and M6G out of the brain.Clinical microdialysis of morphine showed a similar pattern to that observed in the animal studies, with asignificantly longer half-life in uninjured (73 min) or injured (77 min) brain tissue, than in blood (28 min) andadipose tissue (27 min).
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| 3. |
- Ederoth, Per, et al.
(författare)
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Blood-brain barrier transport of morphine in patients with severe brain trauma
- 2004
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 57:4, s. 427-435
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Tidskriftsartikel (refereegranskat)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. |
- Kuypers, Dirk R., et al.
(författare)
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Mycophenolic Acid Exposure after Administration of Mycophenolate Mofetil in the Presence and Absence of Ciclosporin in Renal Transplant Recipients
- 2009
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Ingår i: Clinical Pharmacokinetics. - 0312-5963. ; 48:5, s. 329-341
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Tidskriftsartikel (refereegranskat)abstract
- Background and objective: The pharmacokinetics of mycophenolic acid (MPA) are complex, with large interindividual variability over time. There are also well documented interactions with ciclosporin, and assessment of MPA exposure is therefore necessary when reducing or stopping ciclosporin therapy. Here we report on the pharmacokinetic and pharmacodynamic behaviour of MPA in renal transplant patients on standard dose, reduced dose and no ciclosporin. Study design: The CAESAR study, a prospective 12-month study in primary renal allograft recipients, was designed to determine whether mycophenolate mofetil-based regimens containing either low-dose ciclosporin or low-dose ciclosporin withdrawn by 6 months could minimize nephrotoxicity and improve renal function without an increase in acute rejection compared with a mycophenolate mofetil-based regimen containing standard-dose ciclosporin. Patients and methods: A subset of patients from the CAESAR study contributed to this pharmacokinetic analysis of MPA exposure. Blood samples were taken over one dosing interval on day 7 and at months 3, 7 and 12 post-transplantation. The sampling timepoints were predose, 20, 40 and 75 minutes and 2, 3, 4, 6, 9 and 12 hours after mycophenolate mofetil dosing. Assessments included plasma concentrations of MPA and mycophenolic acid glucuronide (MPAG) and ciclosporin trough concentrations. The area under the plasma concentration-time curve (AUC) from 0 to 12 hours (AUC(12)) for MPA was the primary pharmacokinetic parameter, and the AUC12 for MPAG was the secondary parameter. Results: In total, 536 de novo renal allograft recipients were randomized in the CAESAR study. Of these, 114 patients were entered into the pharmacokinetic substudy and 110 patients contributed to the pharmacokinetic analysis. There was a rapid rise in MPA concentrations (median time to peak concentration 0.72-1.25 hours). At day 7 and month 3, the MPA AUC12 values were similar in the ciclosporin withdrawal and low-dose ciclosporin groups (patients with the same ciclosporin target concentrations to month 6), while at 7 and 12 months, the values in the ciclosporin withdrawal group were higher than in the low-dose group (19.9% and 30.2% higher, respectively). MPA AUC12 values in the standard-dose ciclosporin group were lower than in the other groups at all timepoints and increased over time. At all timepoints, the MPA peak plasma concentration was similar in all groups, and the MPAG concentrations rose more slowly than MPA concentrations. The ratio of the AUC from 6 to 12 hours/AUC(12) suggests that an increasing AUC in the ciclosporin withdrawal group is due to an increase in the enterohepatic recirculation. Conclusion: These findings are consistent with the hypothesis that ciclosporin inhibits the biliary secretion and/or hepatic extraction of MPAG, leading to a reduced rate of enterohepatic recirculation of MPA. Several concurrent mechanisms, such as ciclosporin-induced changes in renal tubular MPAG excretion and enhanced elimination of free MPA through competitive albumin binding with MPAG, can also contribute to the altered MPAG pharmacokinetics observed in the presence and absence of ciclosporin.
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