RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 240
OP 245
DO 10.1124/dmd.32.2.240
VO 32
IS 2
A1 Masashi Mise
A1 Seiji Yadera
A1 Michiaki Matsuda
A1 Takanori Hashizume
A1 Satoshi Matsumoto
A1 Yoshiaki Terauchi
A1 Toshihiko Fujii
YR 2004
UL http://dmd.aspetjournals.org/content/32/2/240.abstract
AB 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