Improved brain delivery of a nonsteroidal anti-inflammatory drug with a synthetic glyceride ester: a preliminary attempt at a CNS drug delivery system for the therapy of Alzheimer's disease.

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.