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Blood-brain barrier transport of morphine in patients with severe brain trauma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (PKPD)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (PKPD)
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2004 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 57, no 4, 427-435 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2004. Vol. 57, no 4, 427-435 p.
Keyword [en]
blood-brain barrier, brain injury, human, microdialysis, morphine, pharmacokinetics
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-91386DOI: 10.1046/j.1365-2125.2003.02032.xISI: 000220272800008PubMedID: 15025740OAI: oai:DiVA.org:uu-91386DiVA: diva2:164099
Available from: 2004-02-12 Created: 2004-02-12 Last updated: 2013-03-22Bibliographically approved
In thesis
1. Blood-Brain Barrier Transport of Drugs Across Species with the Emphasis on Health, Disease and Modelling
Open this publication in new window or tab >>Blood-Brain Barrier Transport of Drugs Across Species with the Emphasis on Health, Disease and Modelling
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 70 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 307
Pharmaceutical biosciences, Blood-brain barrier, Disease, Microdialysis, Modelling, Transport, Pharmacokinetics, NONMEM, Farmaceutisk biovetenskap
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-4005 (URN)91-554-5879-3 (ISBN)
Public defence
2004-03-05, B41, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2004-02-12 Created: 2004-02-12Bibliographically approved

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