Purpose: To determine the roles of blood-brain barrier (BBB) transport and plasma protein binding in brain uptake of nonsteroidal anti-inflammatory drugs (NSAIDs)-ibuprofen, flurbiprofen, and indomethacin.
Methods: Brain uptake was measured using in situ rat brain perfusion technique.
Results: [14C]Ibuprofen, [3H]flurbiprofen, and [14C]indomethacin were rapidly taken up into the brain in the absence of plasma protein with BBB permeability-surface area products (PS(u)) to free drug of (2.63 +/- 0.11) x 10(-2), (1.60 +/- 0.08) x 10(-2), and (0.64 +/- 0.05) x 10(-2) mL s(-1) g(-1) (n = 9-11), respectively. BBB [14C]ibuprofen uptake was inhibited by unlabeled ibuprofen (Km = 0.85 +/- 0.02 mM, Vmax = 13.5 +/- 0.4 nmol s(-1) g(-1)) and indomethacin, but not by pyruvate, probenecid, digoxin, or valproate. No evidence was found for saturable BBB uptake of [3H]flurbiprofen or [14C]indomethacin. Initial brain uptake for all three NSAIDs was reduced by the addition of albumin to the perfusion buffer. The magnitude of the brain uptake reduction correlated with the NSAID free fraction in the perfusate.
Conclusions: Free ibuprofen, flurbiprofen, and indomethacin rapidly cross the BBB, with ibuprofen exhibiting a saturable component of transport. Plasma protein binding limits brain NSAID uptake by reducing the free fraction of NSAID in the circulation.