TY - JOUR T1 - Metabolism of 2,6-Dichloro-4-(3,3-dichloroallyloxy)phenyl 3-[5-(trifluoromethyl)-2-pyridyloxy]propyl Ether (Pyridalyl) in Rats after Repeated Oral Administration and a Simple Physiologically Based Pharmacokinetic Modeling in Brown and White Adipose Tissues JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 824 LP - 832 DO - 10.1124/dmd.109.031914 VL - 38 IS - 5 AU - Hirohisa Nagahori AU - Haruyuki Matsunaga AU - Yoshitaka Tomigahara AU - Naohiko Isobe AU - Hideo Kaneko Y1 - 2010/05/01 UR - http://dmd.aspetjournals.org/content/38/5/824.abstract N2 - Male and female Sprague-Dawley rats received repeated oral administration of 14C-2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3- [5-(trifluoromethyl)-2-pyridyloxy]propyl ether (14C-pyridalyl) at 5 mg/kg/day for 14 consecutive days, and 14C excretion, 14C concentration in tissues, and the metabolic fate were determined. Most 14C was excreted into feces. The 14C concentrations in the blood and tissues attained steady-state levels at days 6 to 10, whereas those in white adipose tissues increased until day 14. Tissue 14C concentrations were highest in brown and white adipose tissue (38.37–57.50 ppm) but were 5.60 ppm or less in all the other tissues. Total 14C residues in blood and tissues on the 27th day after the first administration accounted for 2.6 to 3.2% of the total dose. A major fecal metabolite resulted from O-dealkylation. Analysis of metabolites in tissues revealed that the majority of 14C in perirenal adipose tissue and lungs was pyridalyl, accounting for greater than 90 and 60%, respectively, of the total, whereas a major metabolite in whole blood, kidneys, and liver was a dehalogenated metabolite. The experimental data were simulated with simple physiologically based pharmacokinetics using four-compartment models with assumption of lymphatic absorption and membrane permeability in adipose tissues. The different kinetics in brown and white adipose tissues was reasonably predicted in this model, with large distribution volume in adipose tissues and high hepatic clearance in liver. Sex-related difference of pyridalyl concentration in liver was considered to be a result of different unbound fraction times the hepatic intrinsic clearance (f × CLint) of 1.8 and 12 l/h for male and female, respectively. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -