INFLUENCE OF AGE ON THE DISPOSITION AND RENAL HANDLING OF ENPROFYLLINE IN RATS

he effects of ageing on the pharmacokinetics, renal handling and protein binding of enprofylline were investigated in 6-, 13- and 18-month-old male Fischer 344 rats. Concentrations of enprofylline in plasma and urine were determined by HPLC, and pharmacokinetic parameters were estimated by model-independent methods. No significant differences in the volume of distribution, systemic clearance of enprofylline or urinary recovery of unchanged enprofylline ( > 85%) were observed among any of the groups of rats. The dissociation constant and free fatty acid concentration in plasma increased with age. Age-dependent decreases in the systemic clearance for unbound drug were observed, and the volume of distribution for unbound drug tended to decrease with age. The ratio of systemic clearance for unbound drug to the glomerular filtration rate (GFR) decreased with ageing. Ageing was associated with decreases in the apparent maximum capacity of transport (V-max) (223.33, 160.24 and 142.98 mu g min(-1) kg(-1) for 6-, 13- and 18-month-old rats, respectively) and in the tubular secretory intrinsic clearance (V-max/K-m) of enprofylline (75.45, 51.03 and 44.13 mL min(-1) kg(-1), respectively), while a slight change in the Michaelis-Menten constant (K-m) was observed. These results indicate that the mechanism responsible for age-related changes in the disposition and renal handling of enprofylline may be responsible for a decrease in the ability of the tubular anion transport system.