Premium
Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin
Author(s) -
Sawamura Ryoko,
Sakurai Hidetaka,
Wada Naoya,
Nishiya Yumi,
Honda Tomoyo,
Kazui Miho,
Kurihara Atsushi,
Shinagawa Akira,
Izumi Takashi
Publication year - 2015
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.1945
Subject(s) - human skin , metabolite , prodrug , chemistry , active metabolite , in vitro , pharmacokinetics , transdermal , in vivo , enzyme , pharmacology , permeation , drug , biochemistry , medicine , biology , genetics , microbiology and biotechnology , membrane
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 K m value was calculated to be 10.3 m m 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 K m and V max values were 7.30 m m 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.