1,3-Diacetyl-2-ketoprofen glyceride (DAKG), a
prodrug of
ketoprofen, was synthesized as a model compound in our attempt to develop a central nervous system (CNS) drug delivery system to treat
Alzheimer's disease. The primary purpose of the present study is to test whether DAKG improves the delivery of
ketoprofen to the brain and to quantitatively evaluate several factors that influence the brain distribution of this
prodrug. ddY mice were injected with either
ketoprofen or DAKG at a dose of 40 micromol/kg and then the plasma and brain pharmacokinetics of these agents were assessed. The brain uptake clearance of
ketoprofen and DAKG across the BBB was measured by in situ mouse brain perfusion. In addition, the efflux permeability of
ketoprofen through the BBB was evaluated using the in vivo mouse brain microdialysis technique. The in vivo metabolism of DAKG in the brain was assessed by a short infusion into the internal carotid artery coupled with the brain metabolism index (BMI) method. Administration of DAKG produced an approximately 3-fold increase in the area under the brain concentration - time curve of
ketoprofen, compared with administration of
ketoprofen itself. The brain uptake clearance (CL(in) ) of
ketoprofen across the BBB was 0.0308 +/- 0.0046 mL/min/g whereas the CL(in) of DAKG was 1.60 +/- 0.16 mL/min/g, suggesting a marked increase in BBB permeability following lipidization of
ketoprofen. The BMI method confirmed that DAKG is taken up by the brain to rapidly release
ketoprofen in a dose-dependent manner. The in vitro metabolism studies revealed that isolated bovine brain capillaries as well as whole brain homogenate have the hydrolysis activity to DAKG. In addition, the brain concentration of
ketoprofen after DAKG administration was maintained for a significant period following co-administration of
probenecid. These results suggest that DAKG improves the delivery of
ketoprofen to the brain, and this improved delivery is due to avid uptake of DAKG across the BBB followed by rapid hydrolysis to
ketoprofen within the brain. The
ketoprofen produced in the brain was probably cleared by the active efflux system operating in the BBB. Significant inhibition of this efflux system by co-administration of
probenecid could result in a sustained concentration of
ketoprofen in the brain following DAKG administration.