Received for publication July 5, 2006.
Revised November 27, 2006.
Accepted for publication November 28, 2006.

MODE OF ADMINISTRATION DEPENDENT BRAIN UPTAKE OF INDOMETHACIN: SUSTAINED SYSTEMIC INPUT INCREASES BRAIN INFLUX

Abstract

NSAIDs, including indomethacin, have been found in both epidemiological and clinical studies to reduce the prevalence and severity of Alzheimer's disease. However, long-term use of indomethacin is limited by significant gastrointestinal and renal toxicities. An indomethacin prodrug that delivers low and continuous blood levels of the drug showed a superior safety profile and similar efficacy in comparison to equivalent dose of free indomethacin due to limited systemic exposure and preferred brain uptake. The purpose of the present investigation was to evaluate whether sustained systemic input causes an increased brain influx in comparison to rapid input of the drug. Oral indomethacin, indomethacin prodrug or intravenous indomethacin infusion were administered to rats. The infusion was designed to mimic the plasma indomethacin levels resulting from the prodrug. The resultant blood levels and brain indomethacin uptake were evaluated. The brain indomethacin concentrations 8 hours after indomethacin administration were 0.45, 0.3 and 0.31µg/g following the oral indomethacin, oral prodrug and the intravenous infusion, respectively. The corresponding plasma concentrations were 14.1, 4.1 and 4µg/ml. Therefore, brain vs. plasma indomethacin levels ratios were 2.5-fold higher following slow systemic input of indomethacin in comparison to rapid drug input. In conclusion, indomethacin brain uptake was found to be mode of administration dependent, and a sustained input function increases the drug brain uptake. Thus, these unique results indicate that an appropriate indomethacin controlled release delivery system may induce the desirable brain related pharmacodynamic effects, while avoiding the concentration dependent adverse effects. These findings may contribute to improved therapy in Alzheimer’s disease.

Key words: blood-CNS transport, controlled drug release, drug delivery, pharmacokinetics