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Influence of probenecid on the delivery of morphine-6-glucuronide to the brain
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-91384OAI: oai:DiVA.org:uu-91384DiVA: diva2:164097
Available from: 2004-02-12 Created: 2004-02-12 Last updated: 2010-01-13Bibliographically 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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