title: Cocktail-Dosing Microdialysis Study to Simultaneously Assess Delivery of Multiple Organic-Cationic Drugs to the Brain.
abstract: Brain microdialysis is a powerful tool to estimate brain-to-plasma unbound concentration ratio at the steady state (Kp,uu) of compounds by direct measurement of the unbound concentration in brain interstitial fluid. Here, we evaluated a method to estimate Kp,uu values of multiple organic-cationic drugs simultaneously, by means of brain microdialysis combined with cocktail dosing. Five cationic drugs (diphenhydramine, memantine, oxycodone, pyrilamine, and tramadol), substrates of the proton-coupled organic cation antiport system, were selected as model drugs, and compared under single-dosing and cocktail-dosing conditions. We selected doses of the drugs at which no significant drug-drug interaction occurs at the proton-coupled organic cation antiport system in the blood-brain barrier (BBB). This was confirmed by uptake studies in hCMEC/D3 cells, an in vitro BBB model. The Kp,uu values after cocktail administration were in the range of 1.8-5.2, and were in good agreement with those after single administration. These results suggest that the microdialysis method with cocktail dosing is suitable to estimate Kp,uu values of several cationic drugs simultaneously, if there is no drug-drug interaction during BBB transport. The method could be useful for evaluating drug candidates with high Kp,uu values at an early stage in the development of central nervous system-acting drugs.
authors.affiliation: Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kitamura
authors.affiliation: Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Okura
authors.affiliation: Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Higuchi
authors.affiliation: Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Itabashi, Tokyo 173-8605, Japan. Electronic address: deguchi@pharm.teikyo-u.ac.jp.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Deguchi
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D017551:Microdialysis / Q000379:methods*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004364:Pharmaceutical Preparations
keywords: active transport; blood–brain barrier; cocktail dosing; drug transport; membrane transporter; microdialysis; organic cation transporters