title: Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin.
abstract: Loxoprofen (LX) is a prodrug-type non-steroidal anti-inflammatory drug which is used not only as an oral drug but also as a transdermal formulation. As a pharmacologically active metabolite, the trans-alcohol form of LX (trans-OH form) is generated after oral administration to humans. The objectives of this study were to evaluate the generation of the trans-OH form in human in vitro skin and to identify the predominant enzyme for its generation. In the permeation and metabolism study using human in vitro skin, both the permeation of LX and the formation of the trans-OH form increased in a time- and dose-dependent manner after the application of LX gel to the skin. In addition, the characteristics of permeation and metabolism of both LX and the trans-OH form were examined by a mathematical pharmacokinetic model. The Kmvalue was calculated to be 10.3 mm in the human in vitro skin. The predominant enzyme which generates the trans-OH form in human whole skin was identified to be carbonyl reductase 1 (CBR1) by immunodepletion using the anti-human CBR1 antibody. The results of the enzyme kinetic study using the recombinant human CBR1 protein demonstrated that the Kmand Vmaxvalues were 7.30 mm and 402 nmol/min/mg protein, respectively. In addition, it was found that no unknown metabolites were generated in the human in vitro skin. This is the first report in which LX is bioactivated to the trans-OH form in human skin by CBR1. Copyright © 2015 John Wiley & Sons, Ltd.
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Sawamura
authors.affiliation: Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Sakurai
authors.affiliation: Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Wada
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nishiya
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Japan.
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Honda
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Kazui
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kurihara
authors.affiliation: Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shinagawa
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
keywords: NSAID; active metabolite; carbonyl reductase 1; human skin