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Research ArticleArticle

POLYMORPHIC EXPRESSION OF CYP1A2 LEADING TO INTERINDIVIDUAL VARIABILITY IN METABOLISM OF A NOVEL BENZODIAZEPINE RECEPTOR PARTIAL INVERSE AGONIST IN DOGS

Masashi Mise, Seiji Yadera, Michiaki Matsuda, Takanori Hashizume, Satoshi Matsumoto, Yoshiaki Terauchi and Toshihiko Fujii
Drug Metabolism and Disposition February 2004, 32 (2) 240-245; DOI: https://doi.org/10.1124/dmd.32.2.240
Masashi Mise
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Seiji Yadera
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Michiaki Matsuda
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Takanori Hashizume
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Satoshi Matsumoto
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Yoshiaki Terauchi
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Toshihiko Fujii
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Abstract

5-(3-Methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine (AC-3933) is a novel cognitive enhancer with central benzodiazepine receptor partial inverse agonistic activity. AC-3933 is predominantly metabolized to hydroxylated metabolite [SX-5745; 3-(5-hydroxymethyl-1,2,4-oxadiazol-3-yl)-5-(3-methoxyphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridine] in dog. Initially, we found that there is considerable interindividual variability in AC-3933 hydroxylation in dogs and that dogs could be phenotyped as extensive metabolizer (EM) and poor metabolizer (PM). Then, to clarify the cause of AC-3933 polymorphic hydroxylation in dogs, in vitro studies were carried out using liver microsomes from EM and PM dogs. Our results show that AC-3933 hydroxylation clearance in PM dogs was much lower than that in EM dogs (0.2 versus 10.8-20.5 μl/min/mg, respectively). In addition, AC-3933 hydroxylation was significantly inhibited by α-naphthoflavone, a CYP1A inhibitor, and by anti-CYP1A2 antibodies, indicating that CYP1A2 was responsible for the polymorphic hydroxylation of AC-3933 in dogs. Furthermore, immunoblotting results have shown that although CYP1A2 protein was not detected in PM dogs (<0.86 pmol/mg), CYP1A2 content in EM dogs was prominent (6.1-13.0 pmol/mg). These results indicate that AC-3933 polymorphic hydroxylation arises from the polymorphic expression of CYP1A2 in dogs, which might involve genetic polymorphism of the CYP1A2 gene.

Footnotes

  • ↵1 Abbreviations used are: P450, cytochrome P450; AC-3933, 5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine; [14C]AC-3933, (5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-[7-14C]-1,6-naphthyridine; SX-5745, 3-(5-hydroxymethyl-1,2,4-oxadiazol-3-yl)-5-(3-methoxyphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridine; SX-5773, 5-(3-hydroxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine; SX-6088, 5-(3-methoxyphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylic acid; EM, extensive metabolizer; PM, poor metabolizer; C3h, concentration at 3 h after administration; HPLC, high-performance liquid chromatography; EROD, ethoxyresorufin O-deethylase; POD, phenacetin O-deethylase; ECOD, ethoxycoumarin O-deethylase; APND, aminopyrine N-demethylase; AUC0-24, area under concentration-time curve from zero to 24 h.

    • Received August 5, 2003.
    • Accepted October 31, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (2)
Drug Metabolism and Disposition
Vol. 32, Issue 2
1 Feb 2004
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Research ArticleArticle

POLYMORPHIC EXPRESSION OF CYP1A2 LEADING TO INTERINDIVIDUAL VARIABILITY IN METABOLISM OF A NOVEL BENZODIAZEPINE RECEPTOR PARTIAL INVERSE AGONIST IN DOGS

Masashi Mise, Seiji Yadera, Michiaki Matsuda, Takanori Hashizume, Satoshi Matsumoto, Yoshiaki Terauchi and Toshihiko Fujii
Drug Metabolism and Disposition February 1, 2004, 32 (2) 240-245; DOI: https://doi.org/10.1124/dmd.32.2.240

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Research ArticleArticle

POLYMORPHIC EXPRESSION OF CYP1A2 LEADING TO INTERINDIVIDUAL VARIABILITY IN METABOLISM OF A NOVEL BENZODIAZEPINE RECEPTOR PARTIAL INVERSE AGONIST IN DOGS

Masashi Mise, Seiji Yadera, Michiaki Matsuda, Takanori Hashizume, Satoshi Matsumoto, Yoshiaki Terauchi and Toshihiko Fujii
Drug Metabolism and Disposition February 1, 2004, 32 (2) 240-245; DOI: https://doi.org/10.1124/dmd.32.2.240
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