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 K value 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 K and V values 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.

Topical application of anthranilate derivatives ameliorates psoriatic inflammation in a mouse model by inhibiting keratinocyte‐derived chemokine expression and neutrophil infiltration

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The modulation of carbonyl reductase 1 by polyphenols

“…The major metabolic pathway involved in the biotransformation of loxoprofen, a prodrugtype non-steroidal anti-inflammatory drug used orally and topically, is carbonyl reduction to a pharmacologically active alcohol metabolite (Ohara et al, 1995). The predominant enzyme which catalyzes this reaction in human liver as well as in skin was identified to be CBR1 (Ohara et al, 1995;Sawamura et al, 2015). In contrast, the structurally similar drug ketoprofen is metabolized exclusively by AKRs (Ohara et al, 1995).…”