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An integrated model for the analysis of pharmacokinetic data from microdialysis experiments
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
2004 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 21, no 9, 1698-1707 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2004. Vol. 21, no 9, 1698-1707 p.
Keyword [en]
Animals, Blood-Brain Barrier/drug effects, Comparative Study, Microdialysis, Models; Biological, Morphine/pharmacokinetics, Pharmacokinetics, Probenecid/pharmacology, Rats, Research Support; Non-U.S. Gov't
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-91387DOI: 10.1023/B:PHAM.0000041468.00587.c6PubMedID: 15497699OAI: oai:DiVA.org:uu-91387DiVA: diva2:164100
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
Opponent
Supervisors
Available from: 2004-02-12 Created: 2004-02-12Bibliographically approved

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Hammarlund-Udenaes, MargaretaJonsson, Niclas E.

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