Blood-Brain Barrier Transport of Drugs Across Species with the Emphasis on Health, Disease and Modelling

• Main Author: Tunblad, Karin
• Format: Doctoral Thesis
• Language: English
• Published: Uppsala universitet, Avdelningen för farmakokinetik och läkemedelsterapi 2004
• Subjects: Pharmaceutical biosciences; Blood-brain barrier; Disease; Microdialysis; Modelling; Transport; Pharmacokinetics; NONMEM; Farmaceutisk biovetenskap; Biopharmacy; Biofarmaci
• Online Access: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4005; http://nbn-resolving.de/urn:isbn:91-554-5879-3

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.