Enzymologic and Pharmacologic Profile of Loxoprofen Sodium and Its Metabolites

Noguchi, Masahiro; Kimoto, Aishi; Gierse, James K.; Walker, Mark C.; Zweifel, Ben S.; Nozaki, Kazutoshi; Sasamata, Masao

doi:10.1248/bpb.28.2075

Cited by 28 publications

(18 citation statements)

References 19 publications

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“…As it has been reported that the edema induced by carrageenin involved PGE 2 and NO production, 21,22) it is suggested that the inhibitory effect of CSE in Fig. 2 was due to 2, 6, and 7 as well as 1.…”

Section: Discussionmentioning

confidence: 80%

Anti-inflammatory Constituents of Sappan Lignum

Washiyama

Sasaki

Hosokawa

et al. 2009

Biological & Pharmaceutical Bulletin

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Caesalpinia sappan L. (Leguminosae) is distributed inSoutheast Asia, and its heartwood, Sappan Lignum, is famous as a red dyestuff. Sappan Lignum is also used as herbal medicine for inflammation or improvement for blood circulation. 1,2) In Japan, Sappan Lignum is newly listed in the 15th Japanese Pharmacopoeia. 3)Aside from brazilin (1) and brazilein, the known constituents of Sappan Lignum, we have isolated sappanchalcone (2) and protosappanins A-E (3-7), which are dibenzoxocin derivatives, and elucidated their structures (Fig. 1). [4][5][6][7][8][9] Pharmacological studies of Sappan Lignum focusing on its vasorelaxation 10) or immunosuppressive effect 11) have concluded that 1 is the active compound. Compound 1 alone was reported to show anti-inflammatory effect, 12,13) lensaldose reductase inhibitory effect, 14) and anti-hepatotoxic effect.15) However, there are few pharmacological studies of other compounds except ours. We previously performed an in vitro assay for 1, brazilein, 2, 3, 4, and 5, and clarified such properties as inhibition of nitric oxide (NO) production and inducible NO synthase gene expression, as well as free radical scavenging and antioxidant activity.16) The results suggested that Sappan Lignum contained active compounds other than 1 that showed anti-inflammatory effect.In this study, we performed an in vitro assay for 2, 4) 3, 5)4, 6) 5, 7) 6 (isomeric mixtures), 8) and 7 (isomeric mixtures of E-1 and E-2) 9) to determine the mechanism underlying their inhibitory effects on NO and prostaglandin E 2 (PGE 2 ) production and their suppressive effects on the mRNA expression of typical chemical mediators of inflammation: tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), and inducible NO synthase (iNOS). We then performed an in vivo assay for methanolic extract of Sappan Lignum (CSE) and 1 to evaluate their anti-inflammatory effect on carrageenin-induced mouse paw edema in order to estimate whether or not 1 was the only active constituent of CSE. MATERIALS AND METHODSMaterials Brazilin (1, 5.1% from CSE), sappanchalcone (2, 0.38%), protosappanin A (3, 0.15%), protosappanin B (4, 0.80%), protosappanin C (5, 0.48%), protosappanin D (6, 0.15%), and protosappanin E (7, 0.32%) were isolated from Sappan Lignum purchased from Uchida Wakanyaku Co., Ltd. (Lot. No. 313116, December 27, 2006 We performed an in vitro assay for seven compounds from methanolic extract of Sappan Lignum (CSE) that inhibit the chemical mediators of inflammation using the J774.1 cell line: brazilin (1), sappanchalcone (2), protosappanin A (3), protosappanin B (4), protosappanin C (5), protosappanin D (6), and protosappanin E (7). Those compounds were evaluated for their inhibitory effects on nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) production and their suppressive effects on tumor necrosis factor-a a (TNF-a a), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) mRNA expression. As a result, we clarified that 1 inhibited NO production, and almost no...

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Section: Discussionmentioning

confidence: 80%

Anti-inflammatory Constituents of Sappan Lignum

Washiyama

Sasaki

Hosokawa

et al. 2009

Biological & Pharmaceutical Bulletin

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“…Some examples are loxoprofen (Tanaka et al, 1983;Noguchi et al, 2005), befunolol (Tohno et al, 1979), and acetohexamide ( Fig. 12A) (McMahon et al, 1965).…”

Section: Carbonyl Reductases/aldo-keto Reductasesmentioning

confidence: 99%

Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

Foti

Dalvie

2016

Drug Metabolism and Disposition

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The drug-metabolizing enzymes that contribute to the metabolism or bioactivation of a drug play a crucial role in defining the absorption, distribution, metabolism, and excretion properties of that drug. Although the overall effect of the cytochrome P450 (P450) family of drug-metabolizing enzymes in this capacity cannot be understated, advancements in the field of non-P450-mediated metabolism have garnered increasing attention in recent years. This is perhaps a direct result of our ability to systematically avoid P450 liabilities by introducing chemical moieties that are not susceptible to P450 metabolism but, as a result, may introduce key pharmacophores for other drug-metabolizing enzymes. Furthermore, the effects of both P450 and non-P450 metabolism at a drug's site of therapeutic action have also been subject to increased scrutiny. To this end, this Special Section on Emerging Novel Enzyme Pathways in Drug Metabolism will highlight a number of advancements that have recently been reported. The included articles support the important role of non-P450 enzymes in the clearance pathways of U.S. Food and Drug Administration-approved drugs over the past 10 years. Specific examples will detail recent reports of aldehyde oxidase, flavin-containing monooxygenase, and other non-P450 pathways that contribute to the metabolic, pharmacokinetic, or pharmacodynamic properties of xenobiotic compounds. Collectively, this series of articles provides additional support for the role of non-P450-mediated metabolic pathways that contribute to the absorption, distribution, metabolism, and excretion properties of current xenobiotics.

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“…Formalin has been reported to induce inflammation via similar mechanism as described for carrageenan (Joseph et al, 2009). However, non-steroidal anti-inflammatory drugs such as aspirin, indomethacin and diclofenac are known to mediate their anti-inflammatory action via inhibition of these phases of inflammatory response (Vane and Booting, 1987;Noguchi et al, 2005).…”

Section: Pharmacological Activity Of Some Plants Used In the Treatmenmentioning

confidence: 99%