title: Novel revelation of warfarin resistant mechanism in roof rats (Rattus rattus) using pharmacokinetic/pharmacodynamic analysis.
abstract: Roof rats (Rattus rattus) live mainly in human habitats. Heavy use of rodenticides, such as warfarin, has led to the development of drug resistance, making pest control difficult. There have been many reports regarding mutations of vitamin K epoxide reductase (VKOR), the target enzyme of warfarin, in resistant rats. However, it has been suggested there are other mechanisms of warfarin resistance. To confirm these possibilities, closed colonies of warfarin-susceptible roof rats (S) and resistant rats from Tokyo (R) were established, and the pharmacokinetics/pharmacodynamics of warfarin in rats from both colonies was investigated. R rats had low levels of warfarin in serum and high clearance activity. These rats can rapidly metabolize warfarin by hydroxylation. The levels of accumulation in the organs were lower than those of S rats. R rats administered warfarin showed high expression levels of CYP2B, 2C, and 3A, which play roles in warfarin hydroxylation, and may explain the high clearance ability of R rats. The mechanism of warfarin resistance in roof rats from Tokyo involved not only mutation of VKOR but also high clearance ability due to high levels of CYP2B, 2C and 3A expression possibly induced by warfarin.
authors.affiliation: Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo 060-0818, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo 060-0818, Japan; Water Research Group, Unit for Environmental Sciences and Management, North-West University, Potchefstroom, South Africa.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ikenaka
authors.affiliation: Technical Research Laboratory, Ikari Corporation, Chiba 260-0844, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tanikawa
authors.affiliation: Technical Research Laboratory, Ikari Corporation, Chiba 260-0844, Japan.
authors.forename: Kazuyuki D
authors.initials: KD
authors.lastname: Tanaka
authors.affiliation: Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo 060-0818, Japan.
authors.forename: Shouta M M
authors.initials: SM
authors.lastname: Nakayama
authors.affiliation: Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo 060-0818, Japan.
authors.forename: Hazuki
authors.initials: H
authors.lastname: Mizukawa
authors.affiliation: Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo 060-0818, Japan. Electronic address: ishizum@vetmed.hokudai.ac.jp.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ishizuka
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics / Q000502:physiology*; D005243:Feces / Q000737:chemistry; D006900:Hydroxylation; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009154:Mutation; D011517:Prothrombin Time; D051381:Rats; D012378:Rodenticides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000652:urine; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000652:urine
chemical_list: D012378:Rodenticides; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D064417:Vitamin K Epoxide Reductases
keywords: Cytochrome P450; Drug resistance; Pharmacokinetics; Rattus rattus; Rodenticide; Warfarin