Polymorphic expression of CYP1A2 leading to interindividual variability in metabolism of a novel benzodiazepine receptor partial inverse agonist in dogs.
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.
Mise
Masashi
M
Pharmacokinetics and Physico-Chemical Property Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Osaka 564-0053, Japan. masashi-mise@dainippon-pharm.co.jp
Yadera
Seiji
S
Matsuda
Michiaki
M
Hashizume
Takanori
T
Matsumoto
Satoshi
S
Terauchi
Yoshiaki
Y
Fujii
Toshihiko
T
D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D058785:GABA-A Receptor Agonists; D006900:Hydroxylation; D015151:Immunoblotting; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D009287:Naphthyridines / Q000097:blood / Q000493:pharmacokinetics*; D018697:Nootropic Agents / Q000097:blood / Q000493:pharmacokinetics*; D010069:Oxadiazoles / Q000097:blood / Q000493:pharmacokinetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D013997:Time Factors
C483032:5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine; D058785:GABA-A Receptor Agonists; D007527:Isoenzymes; D009287:Naphthyridines; D018697:Nootropic Agents; D010069:Oxadiazoles; D019388:Cytochrome P-450 CYP1A2