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Altered brain exposure of morphine in experimental meningitis studied with microdialysis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
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2004 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 48, no 3, 294-301 p.Article in journal (Refereed) Published
Abstract [en]

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 lipopoly-saccharide into the cisterna magna. When meningitis was established, the morphine experiment was repeated.

RESULTS:

The unbound area under the concentration-time curve (AUCu) 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 AUCu 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.

Place, publisher, year, edition, pages
2004. Vol. 48, no 3, 294-301 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-91385DOI: 10.1111/j.0001-5172.2003.0311.xPubMedID: 14982561OAI: oai:DiVA.org:uu-91385DiVA: diva2:164098
Available from: 2004-02-12 Created: 2004-02-12 Last updated: 2017-12-14Bibliographically 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.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 307
Keyword
Pharmaceutical biosciences, Blood-brain barrier, Disease, Microdialysis, Modelling, Transport, Pharmacokinetics, NONMEM, Farmaceutisk biovetenskap
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-4005 (URN)91-554-5879-3 (ISBN)
Public defence
2004-03-05, B41, BMC, Husargatan 3, Uppsala, 09:15
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Available from: 2004-02-12 Created: 2004-02-12Bibliographically approved

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