title: Analysis of the disposition of a novel p38 MAPK inhibitor, AKP-001, and its metabolites in rats with a simple physiologically based pharmacokinetic model.
abstract: 5-[(2-Chloro-6-fluorophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole (AKP-001) is a potent p38 mitogen-activated protein kinase inhibitor that is being developed to specifically target the intestines for the treatment of inflammatory bowel disease. According to the ante-drug concept, AKP-001 was designed to be metabolized to inactive forms via the first-pass metabolism to avoid undesirable systemic exposure. The purpose of this study is to investigate the pharmacokinetic characteristics of AKP-001 and its metabolites (M1 and M2) in rats, utilizing a simple physiologically based pharmacokinetic (PBPK) model. In vitro metabolic activity of AKP-001 in the S9 fraction of rat liver was examined, and plasma concentration-time profiles were developed following intravenous and/or oral administration of AKP-001 and its metabolites. AKP-001 was primarily metabolized to M1; however, M2 was not detected in liver S9 fractions. In accordance with this observation in vitro, M2 was detected in plasma after oral dosing of AKP-001 with a lag time of 1.5 hours, but not after intravenous dosing. To analyze pharmacokinetics in rats in vivo, a simple PBPK model was developed by simultaneous fitting of the plasma concentrations after treatment with AKP-001 and its metabolites. The observed plasma concentration-time profiles of AKP-001 and metabolites were described by the model adequately. Intestinal and systemic exposures of AKP-001 were simulated using the model to assess the relationship between pharmacokinetics and efficacy/safety. Model analysis suggested that oral bioavailability of intestine-targeting ante-drugs should be low to avoid systemic side effects. The pharmacokinetic properties of AKP-001 meet this criterion owing to extensive first-pass metabolism.
authors.affiliation: Pharmacokinetic Research Department, Developmental Research Center (K.S., M.K., M.S., K.M., and A.F.) and Synthetic Research Department, Medicinal Research Center (S.O.), ASKA Pharmaceutical Co. Ltd., Kanagawa, Japan; Pharmacology and Pharmacokinetics (A.H.) and Department of Pharmacy (H.S.), The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Shirota
authors.affiliation: Pharmacokinetic Research Department, Developmental Research Center (K.S., M.K., M.S., K.M., and A.F.) and Synthetic Research Department, Medicinal Research Center (S.O.), ASKA Pharmaceutical Co. Ltd., Kanagawa, Japan; Pharmacology and Pharmacokinetics (A.H.) and Department of Pharmacy (H.S.), The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kaneko
authors.affiliation: Pharmacokinetic Research Department, Developmental Research Center (K.S., M.K., M.S., K.M., and A.F.) and Synthetic Research Department, Medicinal Research Center (S.O.), ASKA Pharmaceutical Co. Ltd., Kanagawa, Japan; Pharmacology and Pharmacokinetics (A.H.) and Department of Pharmacy (H.S.), The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Pharmacokinetic Research Department, Developmental Research Center (K.S., M.K., M.S., K.M., and A.F.) and Synthetic Research Department, Medicinal Research Center (S.O.), ASKA Pharmaceutical Co. Ltd., Kanagawa, Japan; Pharmacology and Pharmacokinetics (A.H.) and Department of Pharmacy (H.S.), The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Minato
authors.affiliation: Pharmacokinetic Research Department, Developmental Research Center (K.S., M.K., M.S., K.M., and A.F.) and Synthetic Research Department, Medicinal Research Center (S.O.), ASKA Pharmaceutical Co. Ltd., Kanagawa, Japan; Pharmacology and Pharmacokinetics (A.H.) and Department of Pharmacy (H.S.), The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Fujikata
authors.affiliation: Pharmacokinetic Research Department, Developmental Research Center (K.S., M.K., M.S., K.M., and A.F.) and Synthetic Research Department, Medicinal Research Center (S.O.), ASKA Pharmaceutical Co. Ltd., Kanagawa, Japan; Pharmacology and Pharmacokinetics (A.H.) and Department of Pharmacy (H.S.), The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ohta
authors.affiliation: Pharmacokinetic Research Department, Developmental Research Center (K.S., M.K., M.S., K.M., and A.F.) and Synthetic Research Department, Medicinal Research Center (S.O.), ASKA Pharmaceutical Co. Ltd., Kanagawa, Japan; Pharmacology and Pharmacokinetics (A.H.) and Department of Pharmacy (H.S.), The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan hisaka@chiba-u.jp.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hisaka
authors.affiliation: Pharmacokinetic Research Department, Developmental Research Center (K.S., M.K., M.S., K.M., and A.F.) and Synthetic Research Department, Medicinal Research Center (S.O.), ASKA Pharmaceutical Co. Ltd., Kanagawa, Japan; Pharmacology and Pharmacokinetics (A.H.) and Department of Pharmacy (H.S.), The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006868:Hydrolysis; D008658:Inactivation, Metabolic; D007275:Injections, Intravenous; D007555:Isoxazoles / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C000600872:AKP-001; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007555:Isoxazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D048051:p38 Mitogen-Activated Protein Kinases