Factors limiting nonsteroidal anti-inflammatory drug uptake and distribution in central nervous system

Several non-selective NSAIDs, including naproxen, ibuprofen, flurbiprofen, and indomethacin, are of interest as neuroprotective agents in cerebral ischemia and neurodegenerative disorders. However, these agents show only limited distribution to the central nervous system (CNS) at normal doses (steady sate brain/plasma concentration = 0.01-0.05) and produce significant gastrointestinal toxicity. CNS therapeutic index for neuroprotection may be enhanced by improved brain delivery. The objective of this dissertation was to determine the factors that limit NSAID uptake and distribution in the CNS. Unidirectional transfer constants (Kin) were measured for brain uptake of [14C]naproxen, [14C]ibuprofen, [3H]flurbiprofen, and [14C]indomethacin using the in situ brain perfusion technique. All four agents showed rapid uptake into brain in the absence of plasma protein. With the exception of [14C]ibuprofen, the permeability-surface area product (PSu) of the blood-brain barrier (BBB) permeability was independent of perfusate NSAID concentration and unaffected by inhibitors of BBB active efflux. However, brain NSAID uptake was markedly reduced by addition of albumin to the perfusate buffer. Each of the NSAIDs bound with high affinity to albumin. The magnitude of the brain uptake reduction varied directly with the NSAID free fraction (fu) of perfusate buffer. The time course (30 s – 10 min) of [14C]naproxen uptake into brain could be described by a two-compartment model incorporating a Kin for brain uptake, perfusate fu, and. A brain-to-free perfusion fluid naproxen distribution volume (Vbr). The critical role of plasma protein binding in brain naproxen uptake was confirmed in intravenous injection experiments using normal Sprague-Dawley (SDR) and Nagase albuminemic (NAR) rats. In NAR animals, brain [14C]naproxen Kin, steady-state brain distribution space, and serum fu were increased >30 fold in NAR, consistent with the lack of albumin. The difference in CNS [14C]naproxen uptake was primarily attributable to the increase in serum fu. The results demonstrate that naproxen, ibuprofen, flurbiprofen, and indomethacin readily cross the BBB but distribute to only a limited extent in the CNS due to tight plasma protein binding. Improved NSAID brain delivery may be achievable by structural alterations in the NSAID molecule to improved brain distribution Vbr and reduce plasma protein binding.