Pharmaceutical Sciences Allen J. Sedman Lectureship Series presents Dr. Tetsuya Terasaki
Please join us for the Pharmaceutical Sciences Allen J. Sedman Lectureship Series presenting Dr. Tetsuya Terasaki on "Pharmacoproteomics (PPx) of the CNS Barriers: Recent Advance and Prospect.”
The lecture series will be held annually and will emphasize the following fields of study: pharmacokinetics-pharmacodynamics, pharmacometrics, biopharmaceutics, drug metabolism, drug transport and targeting, and pharmacogenomics.
Speaker Bio: Tetsuya Terasaki, PhD
Dr. Terasaki is the Division of Membrane Transport and Drug Targeting at the Graduate School of Pharmaceutical Sciences at Tohuku University in Sendai, Japan.
Topic of Discussion: Pharmacoproteomics (PPx) of the CNS Barriers: Recent Advance and Prospect
Substrate exchange between blood and central nervous system (CNS) is strictly regulated by the function of brain barriers, i.e., the blood-brain barrier (BBB), the blood-spinal cord barrier (BSB), the blood-cerebrospinal fluid barrier (BCB), and the blood-arachnoid barrier (BAB). Unbound drug concentration in the brain interstitial fluid (BIF) and/or the cerebrospinal fluid (CSF) is a key factor for the rational prediction of drug sensitivity to the CNS, while it is not so easy. Because the active transport function in these barriers generates the unbound drug concentration gradient between blood and BIF/CSF. Knowing location and amount of membrane transporter protein is crucial for the prediction of in vivo drug transport activity, therefore it is important to measure the transporter protein expression in the brain barriers. We have established a method to quantify proteins by LC-MS/MS combined with the in silico criteria of peptide selection among the peptides produced by tryptic digestion (1).
Similarity and difference of the transporter protein expression have been elucidated by comparing that of immortalized human BBB model (D3 cell line) versus isolated brain capillaries in human (2,3). Interspecies differences have also been exhibited for mouse (1), rat (4), dog (5), marmoset (4), cynomolgus monkey (6) and human (2). Assuming the intrinsic efflux transport activity of P-gp determined by in vitro mdr1a gene transfected cell line is same to that of in vivo BBB, we have succeeded to predict the unbound drug concentration gradient between BIF and plasma in the normal (7), epileptic mouse (8) and cynomolgus monkey (9) based on the pharmacokinetic model constructed. For the understanding of functional changes of the BBB transporter, we have examined the effect of tumor necrosis factor-a (TNF-a; an inflammatory mediator) on the BBB P-gp activity by phosphor-proteomics (10). Actin Filament-Associated Protein-1 (AFAP-1) is a key mediator in the inflammatory signaling-induced, translocation-independent rapid attenuation of P-gp efflux activity in human BBB, showing difficulties in the prediction of transport activity of in vivo BBB in the diseased states (10).
Contrary to the recent progress of the BBB research, lots of subjects remain to be clarified for the function of BCB, BSB and BAB. One of crucial subjects is, I believe, to clarify functional significance and regulation mechanism of BAB and BSB transport function for the reliable prediction of drug concentration in the CSF.
- Kamiie J, Ohtsuki S, Iwase R, et al., Pharm Res, 25: 1469-1483 (2008).
- Uchida Y, Ohtsuki S, Katsukura Y, et al., J Neurochem, 117: 333-345 (2011).
- S, Ikeda C, Uchida Y, et al., Mol Pharm, 10: 289-296 (2013).
- Hoshi Y, Uchida Y, Tachikawa M, et al., J Pharm Sci, 102: 3343-3355 (2013).
- Braun C, Sakamoto A, Fuchs H, et al., Mol Pharm, Accepted for publication.
- Ito K, Uchida Y, Ohtsuki S, et al., J. Pharm. Sci., 100: 3939-3950 (2011).
- Uchida Y, Ohtsuki S, Kamiie J, et al., J Pharmacol Exp Ther, 339: 579-588 (2011).
- Uchida Y, Ohtsuki S, Terasaki T., Drug Metab Dispos, 42: 1719-1726 (2014).
- Uchida Y, Wakayama K, Ohtsuki S, et al., J Pharmacol Exp Ther, 350: 578-588 (2014).
- Hoshi Y, Uchida Y, Tachikawa M, et al., J Neurochem, 141:247-262 (2017).