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

he effects of ageing on the pharmacokinetics, renal handling and prote in binding of enprofylline were investigated in 6-, 13- and 18-month-o ld male Fischer 344 rats. Concentrations of enprofylline in plasma and urine were determined by HPLC, and pharmacokinetic parameters were es timated by model-independent methods. No significant differences in th e volume of distribution, systemic clearance of enprofylline or urinar y recovery of unchanged enprofylline ( > 85%) were observed among any of the groups of rats. The dissociation constant and free fatty acid c oncentration 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 rati o 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, res pectively) 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), respectiv ely), while a slight change in the Michaelis-Menten constant (K-m) was observed. These results indicate that the mechanism responsible for a ge-related changes in the disposition and renal handling of enprofylli ne may be responsible for a decrease in the ability of the tubular ani on transport system.