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, Toshihiko Fujii

Pharmacokinetics and Physico-Chemical Property Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Osaka 564-0053, Japan. masashi-mise@dainippon-pharm.co.jp

Drug metabolism and disposition: the biological fate of chemicals 2004 Feb

filter terms:

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 microl/min/mg, respectively). In addition, AC-3933 hydroxylation was significantly inhibited by alpha-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.

Citation

Masashi Mise, Seiji Yadera, Michiaki Matsuda, Takanori Hashizume, Satoshi Matsumoto, Yoshiaki Terauchi, Toshihiko Fujii. Polymorphic expression of CYP1A2 leading to interindividual variability in metabolism of a novel benzodiazepine receptor partial inverse agonist in dogs. Drug metabolism and disposition: the biological fate of chemicals. 2004 Feb;32(2):240-5