RT Journal Article
SR Electronic
T1 Elevated Warfarin Metabolism in Warfarin-Resistant Roof Rats (<em>Rattus rattus</em>) in Tokyo
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 62
OP 66
DO 10.1124/dmd.106.011775
VO 35
IS 1
A1 Mayumi Ishizuka
A1 Fumie Okajima
A1 Tsutomu Tanikawa
A1 Heewon Min
A1 Kazuyuki D. Tanaka
A1 Kentaro Q. Sakamoto
A1 Shoichi Fujita
YR 2007
UL http://dmd.aspetjournals.org/content/35/1/62.abstract
AB Wild roof rats (Rattus rattus) live in proximity to human habitats, and they may carry numerous pathogens of infectious diseases. Pest control is important for public health, and warfarin is a commonly used rodenticide worldwide. However, continual use of warfarin may cause drug resistance in rodents and lead to failure of their control, especially in urbanized areas. In warfarin-resistant rats, the warfarin level in plasma was significantly lower after oral administration than that in the control warfarin-sensitive rats. Warfarin is metabolized by cytochrome P450 (P450), and hydroxylation of warfarin by P450 isoforms was significantly higher in warfarin-resistant rats (2-fold). Western blot analysis indicated that the level of CYP3A2 expression in warfarin-resistant rats was significantly larger than in warfarin-sensitive rats. The NADPH-P450 reductase activities in resistant rats were 8-fold higher than those in sensitive rats. In vivo, the administration of the P450 potent inhibitor proadifen (SKF-525A) increased the mortality of warfarin in the warfarin-resistant roof rats. We concluded that the mechanism of warfarin resistance in Tokyo roof rats is caused by increased clearance of warfarin. The American Society for Pharmacology and Experimental Therapeutics