PHARMACOKINETICS OF KETOPROFEN IN RATS - EFFECT OF AGE AND DOSE

The effects of age and dose on the pharmacokinetics of ketoprofen were evaluated in young adult and senescent male Fischer 344 rats following intravenous administration of 2.5 and 10 mg kg-1. Plasma concentrations were measured by HPLC and free ketoprofen determined by equilibrium dialysis. The glucuronidation of ketoprofen was investigated in a preparation of rat liver microsomes and kinetic analysis of UDP-glucuronyltransferase was carried out by determining the initial rate of metabolic activity as a function of ketoprofen concentration. Mean plasma clearance CL(free) and steady-state volume of distribution V(SS(free)) calculated from unbound plasma ketoprofen concentrations were significantly lower in the aged rat, suggesting reduced metabolic activity and decreased ketoprofen binding to tissue components, respectively. Plasma protein binding demonstrated an age-dependent decline due to decreases in both albumin concentration and binding affinity. Thus, plasma clearance CL and steady-state volume of distribution V(SS) changes were insignificant when total plasma concentrations were examined, due to the greater free fraction of ketoprofen in the plasma of senescent rats. The maximal rate of ketoprofen glucuronidation by hepatic microsomes was reduced whereas the affinity of the metabolic enzymes for the compound was unaffected by age. Dose had a marked effect on the disposition of ketoprofen as well. Saturation of elimination pathways and tissue binding sites contributed to significant declines in CL(free) and V(SS(free)) with increasing dose. Likewise, concentration-dependent plasma protein binding occurred, reflecting saturation of albumin binding. Thus, changes in the pharmacokinetic parameters based on total drug concentrations were offset by the increase in the unbound fraction of ketoprofen.