title: Physiological models are good tools to predict rat bioavailability of EF5154 prodrugs from in vitro intestinal parameters.
abstract: There are only a few reports on the methods that predict in vivo bioavailability from in vitro intestinal parameters. In the present study, we constructed physiological models where we examined if in vivo rat bioavailability was predictable from in vitro intestinal parameters using prodrugs of EF5154, a potent glycoprotein IIb/IIIa receptor antagonist, and other prodrugs. Apparent fraction absorbed (F(a),pred) was calculated using the physiological models that consist of absorption number calculated from Caco-2 cell membrane permeability (P(app)), and Damkohler number calculated from apparent degradation rate constant (K(dapp)) in rat small intestinal fluid. The predicted rat bioavailability that was calculated from F(a),pred corresponded to the observed rat bioavailability, and root mean square error (RMSE) and squared correlation coefficient (r(2)) were 4.58 and 0.904, respectively, suggesting that the physiological models consisting of the membrane permeability and degradation rate constant are good tools for predicting rat bioavailability of EF5154 prodrugs. As for other prodrugs where the chemical structure of their active forms differs from EF5154, the predicted rat bioavailability was not different from fraction absorbed (or rat bioavailability), suggesting the physiological models are generalized to various prodrugs that are not the substrates for active transporters.
authors.affiliation: Applied Pharmacology Research Labs, Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. masahiro_nomoto@meiji.co.jp
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nomoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tatebayashi
authors.forename: Jun
authors.initials: J
authors.lastname: Morita
authors.forename: Hisashi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Aizawa
authors.forename: Tohru
authors.initials: T
authors.lastname: Kurosawa
authors.forename: Izumi
authors.initials: I
authors.lastname: Komiya
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000502:physiology; D007583:Jejunum / Q000378:metabolism* / Q000502:physiology; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008954:Models, Biological; D015394:Molecular Structure; D010827:Physiology; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics*; D011237:Predictive Value of Tests; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C542361:EF5154; D010879:Piperazines; D011355:Prodrugs