title: The effects of the concentration-dependent erythrocyte distribution of TAK-802, a potent acetylcholinesterase inhibitor, on rat pharmacokinetics.
abstract: The purpose of this study was to investigate the effect of the concentration-dependent erythrocyte distribution of TAK-802, a potent acetylcholinesterase inhibitor, on rat pharmacokinetics. In an ascending oral dose study, the maximum plasma concentration (Cmax) of TAK-802 increased in a dose-dependent manner. The time to reach Cmaxdecreased as the dose increased, whereas the total clearance was independent of the tested dose range. In this intravenous (i.v.) ascending dose study in rats, the apparent distribution volumes at steady state decreased, and the apparent terminal elimination rate constants increased with TAK-802 dose escalation. A marked concentration dependency was observed in an associated in vitro erythrocyte distribution study. The in vitro erythrocyte distribution study results and a relationship analysis between the plasma and blood concentrations of TAK-802 after i.v. dosing revealed that the characteristics of the erythrocyte distribution could be expressed by Langmuir's adsorption formula. The concentration-time profiles of TAK-802 in plasma and whole blood calculated using a nonlinear pharmacokinetic model incorporating the concentration-dependent erythrocyte distribution with optimized parameters fit well to the observed plasma and blood concentration profiles obtained from the i.v. ascending dose study. These results indicate that the concentration-dependent erythrocyte distribution plays a major role in the nonlinear pharmacokinetics of TAK-802 in rats. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa, 251-855, Japan. masaaki.kakehi@takeda.com.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kakehi
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa, 251-855, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tagawa
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa, 251-855, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Goto
authors.affiliation: Analytical Development Laboratories, CMC Center, Takeda Pharmaceutical Co. Ltd, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka, 532-8686, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa, 251-855, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Asahi
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011758:Pyrroles / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D015363:Quinolones / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D002800:Cholinesterase Inhibitors; D011758:Pyrroles; D015363:Quinolones; C496138:8-(3-(1-((3-fluorophenyl)methyl)-4-piperidinyl)-1-oxopropyl)-1,2,5,6-tetrahydro-4H-pyrrolo(3,2,1-ij)quinolin-4-one
keywords: TAK-802; concentration-dependent; erythrocyte distribution; nonlinear PK