N-oxidation of irsogladine by the CYP2C subfamily in the rat, dog, monkey and man

Nakamura, Akio; Hirota, Toshio; Morino, Akira; Shimada, Teruo

doi:10.1080/004982597239976

Cited by 10 publications

(4 citation statements)

References 9 publications

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“…In the current study, the anti-NADPH-P450 reductase 27) inhibited the formation of 6-HNA, demonstrating that the oxidation of 6-MNA is mediated by CYPs. Between human and rat CYP2C isoforms reveals differences in their expression.…”

Section: Discussionsupporting

confidence: 60%

In Vitro Characterization of the Cytochrome P450 Isoforms Involved in the Metabolism of 6-Methoxy-2-napthylacetic Acid, an Active Metabolite of the Prodrug Nabumetone

Matsumoto

Nemoto

Hasegawa

et al. 2011

Biological & Pharmaceutical Bulletin

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Nabumetone, 4-(6-methoxy-2-naphthyl)-butan-2-one, is a nonsteroidal anti-inflammatory drug (NSAID) that has proved effective in the treatment of rheumatoid and osteoarthritis.1) Nabumetone is a prodrug that undergoes extensive first-pass metabolism to 6-methoxy-2-naphthylacetic acid (6-MNA), the major circulating metabolite. 6-MNA is largely responsible for the therapeutic efficacy of nabumetone. It decreases prostaglandin synthesis via inhibition of cyclooxygenase, an enzyme involved in the arachidonic acid conversion pathway.2)The metabolism of 6-MNA has been studied in rats, the major experimental animal, and humans. The primary metabolite of 6-MNA, namely, 6-hydroxy-2-naphthylacetic acid (6-HNA), was detected in urine. About 70% of a radiolabeled dose of nabumetone was recovered within 48 h in urine, mainly as 6-MNA, 6-HNA and their conjugates.3) The 6-O-demethylation of 6-MNA to 6-HNA is known to be a major metabolic pathway (Fig. 1). Although it may be obvious that the cytochrome P450 (CYP) system is involved in this pathway, actual CYP isoforms that are involved have not been identified. Their identification is of considerable clinical importance with regard to potential drug interactions and genetically based individual variations of drug metabolism. To our knowledge, no in vitro study has been conducted with respect to the metabolism of 6-MNA or to obtain specific data on the enzyme(s) involved in its metabolic pathway in vitro using human and rat liver microsomes.The purpose of this study was to elucidate CYP isoforms with regard to the 6-O-demethylase activity, a major metabolic pathway of 6-MNA, in human/rat microsomes and recombinant human CYP enzymes expressed in insect cells in which both human/rat CYP and reduced nicotinamide adenine dinucleotide phosphate (NADPH)-P450 reductase cDNAs had been incorporated. We also examined the inhibition or activation of 6-MNA metabolism by chemical substrates and antibodies. MATERIALS AND METHODSChemicals and Reagents 6-MNA and 6-HNA were supplied by Sanwa Kagaku Kenkyusho (SKK) Co., Ltd. (Nagoya, Japan). Glucose-6-phosphaste and glucose-6-dehydrogenase were obtained from Oriental Yeast (Tokyo, Japan). NADPH and nicotinamide adenine dinucleotide phosphate (NADP) were purchased from Alexis (San Diego, CA, U.S.A.). Mefenamic acid and naproxen were purchased from Tokyo Kasei Kogyo Co. (Tokyo, Japan). Acetonitrile, methanol and cimetidine were purchased from Wako Pure Chemical Industries Ltd. (Tokyo, Japan). Furafylline, troleandomycin, ketoconazole, sulfaphenazole and S-mephenytoin were purchased from Daiichi Pure Chemicals (Tokyo, Japan). Diethyldithiocarbamate and quinidine were pur- The cytochrome P450 (CYP) isoforms that catalyze the oxidation metabolism of 6-methoxy-2-napthylacetic acid (6-MNA), an active metabolite of nabumetone, were studied in rats and humans. Using an extractive reversed-phase HPLC assay with fluorescence detection, monophasic Michaelis-Menten kinetics was obtained for the formation of 6-hydroxy-2-naphthylacetic acid (6-HNA) in liver micr...

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Section: Discussionsupporting

confidence: 60%

In Vitro Characterization of the Cytochrome P450 Isoforms Involved in the Metabolism of 6-Methoxy-2-napthylacetic Acid, an Active Metabolite of the Prodrug Nabumetone

Matsumoto

Nemoto

Hasegawa

et al. 2011

Biological & Pharmaceutical Bulletin

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“…While virtual screening for in silico prediction is one of the promising approaches to shorten screening time, it should be also dependent on the credible assay data (Kraljevic et al, 2004). Although in vivo animal tests are normally considered as more credible assay model rather than cell-based assays (CBAs), many examples of xenobiotics and inter-species differences in physiology and pathology have shown the limitation of animal experiments for drug development targeted to human being (Bun et al, 1999;Nakamura et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Microvalve‐assisted patterning platform for measuring cellular dynamics based on 3D cell culture

Kim

Lee

Kim

et al. 2008

Biotech & Bioengineering

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A microfluidic platform to satisfy both 3D cell culture and cell-based assay is required for credible assay results and improved assay concept in drug discovery. In this article, we demonstrate a microvalve-assisted patterning (MAP) platform to provide a new method for investigating cellular dynamics by generating a linear concentration gradient of a drug as well as to realize 3D cell culture in a microenvironment. The MAP platform was fabricated by multilayer soft lithography and several microvalves made it possible to pattern a cell-matrix (scaffold) and to exchange media solutions without breaking cell-matrix structure in a microchannel. This approach provides not only exact fluids control, bubble removal, and stable solution exchange in a microchannel, but also reliable scaffold fabrication and 3D cell culture. In this study, hepatotoxicity tests with human hepatocellular liver carcinoma cells (HepG2) were also performed in real-time monitoring where cell morphologies exposed to different drug concentrations were observed at a time. Compared to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, the MAP platform could be used to reduce drug amount and assay time for cell-based assays as much as 10 and 3 times, respectively.

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“…Irsogladine is completely absorbed from the gastrointestinal tract and undergoes extensive metabolism in animals and humans [9−11]. The primary metabolic pathways of irsogladine are N-oxidation and hydroxylation catalyzed by P450 [12]. P450 isoforms responsible for the metabolism of irsogladine in humans are not fully identified because human recombinant P450 had little activities for the N-oxidation and hydroxylation [12].…”

Section: Introductionmentioning

confidence: 99%

“…The primary metabolic pathways of irsogladine are N-oxidation and hydroxylation catalyzed by P450 [12]. P450 isoforms responsible for the metabolism of irsogladine in humans are not fully identified because human recombinant P450 had little activities for the N-oxidation and hydroxylation [12]. Of the main P450 isoforms, CYP1A2, CYP2C9 and CYP2E1 had activities for the metabolism of irsogladine [12].…”

Section: Introductionmentioning

confidence: 99%

Effects of Irsogladine on P450-isoform Specific Activities in Human Hepatic Microsomes

Nakamura

Tougou

Kitazumi

et al. 2011

Arzneimittelforschung

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The effects of irsogladine (CAS 84504-69-8) on P450-isoform specific activities in human hepatic microsomes were examined. Irsogladine had little effects on coumarin hydroxylation (CYP2A6), 7-benzyloxyresorufin O-debenzylation (CYP2B6), S-mephenytoin hydroxylation (CYP2C19), bufuralol hydroxylation (CYP2D6), chlorzoxazone hydroxylation (CYP2E1) and nifedipine oxidation (CYP3A4) at concentrations ranging from 10 to 50 pmol/L. However, it inhibited 7-ethoxyresorufin O-deethylation (CYP1A2) and tolbutamide hydroxylation (CYP2C9) with the Ki values of 276 and 156 micromol/L, respectively. This suggests that it is a weak inhibitor of these isoforms. Because the plasma concentrations of irsogladine in humans are much lower than these Ki values, it is unlikely that irsogladine causes drug interactions with other drugs.

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N-oxidation of irsogladine by the CYP2C subfamily in the rat, dog, monkey and man

Cited by 10 publications

References 9 publications

In Vitro Characterization of the Cytochrome P450 Isoforms Involved in the Metabolism of 6-Methoxy-2-napthylacetic Acid, an Active Metabolite of the Prodrug Nabumetone

In Vitro Characterization of the Cytochrome P450 Isoforms Involved in the Metabolism of 6-Methoxy-2-napthylacetic Acid, an Active Metabolite of the Prodrug Nabumetone

Microvalve‐assisted patterning platform for measuring cellular dynamics based on 3D cell culture

Effects of Irsogladine on P450-isoform Specific Activities in Human Hepatic Microsomes

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