TY - JOUR T1 - POLYMORPHIC EXPRESSION OF CYP1A2 LEADING TO INTERINDIVIDUAL VARIABILITY IN METABOLISM OF A NOVEL BENZODIAZEPINE RECEPTOR PARTIAL INVERSE AGONIST IN DOGS JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 240 LP - 245 DO - 10.1124/dmd.32.2.240 VL - 32 IS - 2 AU - Masashi Mise AU - Seiji Yadera AU - Michiaki Matsuda AU - Takanori Hashizume AU - Satoshi Matsumoto AU - Yoshiaki Terauchi AU - Toshihiko Fujii Y1 - 2004/02/01 UR - http://dmd.aspetjournals.org/content/32/2/240.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -