TY - JOUR T1 - Metabolism of Pyridalyl in Rats After Repeated Oral Administration and a Simple PBPK Modeling in Brown and White Adipose Tissues JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.109.031914 SP - dmd.109.031914 AU - Hirohisa Nagahori AU - Haruyuki Matsunaga AU - Yoshitaka Tomigahara AU - Naohiko Isobe AU - Hideo Kaneko Y1 - 2010/01/01 UR - http://dmd.aspetjournals.org/content/early/2010/02/17/dmd.109.031914.abstract N2 - Male and female SD rats received repeated oral administration of 14C-pyridalyl at 5 mg/kg/day daily 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 - 10, while 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 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 - 3.2% of the total dose. A major fecal metabolite was resulting 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, while a major metabolite in whole blood, kidneys, and liver was a dehalogenated metabolite. The experimental data were simulated with a simple physiologically based pharmacokinetics (PBPK) using four compartment models with assumption of lymphatic absorption and membrane permeability in adipose tissues. The different kinetics in brown and white adipose tissues were 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 x CLint) of 1.8 and 12 L/h for male and female, respectively.The American Society for Pharmacology and Experimental Therapeutics ER -