Abstract

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.