Inhibition of prostaglandin synthesis by sodium 2-[4-(2-oxocyclopentylmethyl)phenyl] propionate dihydrate (CS-600), a new anti-inflammatory drug, and its active metabolite in vitro and in vivo

Matsuda, Kazuo; Tanaka, Yorihisa; Ushiyama, Shigeru; Ohnishi, Kiyokata; Yamazaki, Mitsuo

doi:10.1016/0006-2952(84)90720-2

Cited by 45 publications

(21 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to the endogenous substrates, xenobiotics such as haloperidol and anti-cancer anthracyclines (daunorubicin and doxorubicin) [27,28], belong to the substrate of CBR1. Although the metabolism of CBR1 is considered to play an important role in the detoxification of endogenous and xenobiotic ligands in the human body [9], it was found that CBR1 forms the pharmacologically active metabolite (the trans-OH form) with higher potency when compared with the parent drug (LX) [1].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, the trans-OH form was determined in the plasma after the dermal application of LX-G to humans and LX-G showed the pharmacological effect after topical application to patients [3][4][5]. The data of the cis-OH form were not shown because the pharmacological activity of the cis-OH form was weak [1] and its concentrations were very low compared with LX and the trans-OH form as described in the Results section. TESTSKIN was used as the human in vitro skin.…”

Section: Discussionmentioning

confidence: 99%

“…Loxoprofen (LX) is a prodrug of the pharmacologically active trans-alcohol form (trans-OH form), which shows a strong inhibitory effect on prostaglandin synthetase [1]. It was initially marketed as an oral drug, with a strong anti-inflammatory effect against rheumatoid arthritis, backache, tooth pain, etc.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin

Sawamura

Sakurai

Wada

et al. 2015

Biopharm & Drug Disp

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin

Sawamura

Sakurai

Wada

et al. 2015

Biopharm & Drug Disp

View full text Add to dashboard Cite

show abstract

“…The mechanism of this drug of pain alleviation is inhibition of prostaglandin synthesis by transalcohol formation that is reduced intermediate metabolite of 1R-2S loxoprofen in the human body as shown in Fig. 1 [2][3][4]. Since this form has short half life cycle, loxoprofen should be taken frequently as administration of the drug [5].…”

Section: Introductionmentioning

confidence: 99%

The enrichment of loxoprofen enantiomer by 6-columns simulated moving bed chromatography

Yoon

Lee

Kim

et al. 2008

Korean J. Chem. Eng.

View full text Add to dashboard Cite

Simulated moving bed (SMB) chromatography is very useful for the separation of binary systems such as chiral compounds. Because loxoprofen racemate has four enantiomers owing to its two chiral centers, to gain pure enantiomer it is impossible with only one step. To apply enrichment of loxoprofen using SMB, extract and raffinate should be separated as a binary mixture. In order to enrich loxoprofen racemate as binary mixture among four mixtures and to characterize its enantiomer, we performed experiments with two types of columns. When TBB ® column was used as CSP, the mixture of (1 ' R,2S) and (1 ' S,2S) forms was eluted as a raffinate and that of (1 ' R,2R) and (1 ' S,2R) forms was discharged as a extract under linear adsorption isotherm range. When the feed flow rates were 0.1 and 0.3 mL/min, purities of raffinate and extract were 98 and 95%, respectively. In this case, productivity of raffinate was 7.81 g/h·g-CSP and that of extract was 6.95 g/h·g-CSP.

show abstract

“…The inhibitory studies of loxoprofen sodium for prostaglandin synthesis in vivo and in vitro suggested that loxoprofen sodium may exhibit inhibitory activity after the conversion to an active metabolite of (Matsuda, Tanaka, Ushiyama, Ohnishi & Yamazaki, 1984). Although the title compound (2) is the steroisomer of this active metabolite of (1), poor inhibition of prostaglandin synthesis was observed.…”

Section: Introductionmentioning

confidence: 99%

Nonsteroidal antiinflammatory drugs. IV. Structure of (±)-(2SR)-2-{4-[(1RS,2RS)-2-hydroxycyclopentylmethyl]phenyl}propionic acid

Hata¹,

Sato²,

Tamura³

1986

Acta Crystallogr C

View full text Add to dashboard Cite

show abstract

Inhibition of prostaglandin synthesis by sodium 2-[4-(2-oxocyclopentylmethyl)phenyl] propionate dihydrate (CS-600), a new anti-inflammatory drug, and its active metabolite in vitro and in vivo

Cited by 45 publications

References 8 publications

Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin

Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin

The enrichment of loxoprofen enantiomer by 6-columns simulated moving bed chromatography

Nonsteroidal antiinflammatory drugs. IV. Structure of (±)-(2SR)-2-{4-[(1RS,2RS)-2-hydroxycyclopentylmethyl]phenyl}propionic acid

Contact Info

Product

Resources

About