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
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↵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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