Pharmacokinetics

The blood-brain barrier (BBB) protects the brain from potentially harmful substances by preventing their access to the central nervous system (CNS). In addition to the tight junctions between the microvascular endothelial cells and the end-feet of astrocytes, efflux transporters play an important role in protecting the brain from xenobiotic substances. In particular, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), both located at the apical (blood-facing) membranes of the endothelial cells of brain capillaries, are essential for the function of the BBB. On the other hand, P-gp and BCRP can also impede the entry of potential therapeutics to the brain, e.g., anticancer or antiepileptic drugs.

Molecular imaging techniques, such as positron emission tomography (PET) offer the potential for in vivo measurement of function and density of efflux transporters in health and disease. However, useful interpretation of raw PET imaging data in terms of functional parameters of efflux transporters requires adequate kinetic modeling. Frequently, nonlinear multi-compartment models are necessary to assess the time-course of radiotracers in the brain. Such nonlinear models may lead to substantial uncertainties in various parameter estimates, calling for sophisticated stochastic or Bayesian methods.

Publications:

Bauer M, Karch R, Zeitlinger M, Liu J, Koepp MJ, Asselin MC, Sisodiya SM, Hainfellner JA, Wadsak W, Mitterhauser M, Müller M, Pataraia E, Langer O. In vivo P-glycoprotein function before and after epilepsy surgery. Neurology 2014 Oct;83(15):1326-31.

Bauer M, Zeitlinger M, Karch R, Matzneller P, Stanek J, Jäger W, Böhmdorfer M, Wadsak W, Mitterhauser M, Bankstahl JP, Löscher W, Koepp M, Kuntner C, Müller M, Langer O. Pgp-mediated interaction between (R)-[11C]verapamil and tariquidar at the human blood-brain barrier: a comparison with rat data. Clin Pharmacol Ther. 2012 Feb;91(2):227-33.

Bauer M, Karch R, Neumann F, Wagner C, Kletter K, Müller M, Löscher W, Zeitlinger M, Langer O. Assessment of regional differences in tariquidar-induced P-glycoprotein modulation at the human blood-brain barrier. J Cereb Blood Flow Metab. 2010 Mar;30(3):510-5.