Pharmaceutical Research

, Volume 23, Issue 5, pp 873–881 | Cite as

Brain Uptake of Nonsteroidal Anti-Inflammatory Drugs: Ibuprofen, Flurbiprofen, and Indomethacin

  • Jagan Mohan R. Parepally
  • Haritha Mandula
  • Quentin R. SmithEmail author
Research Paper


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.


Brain uptake was measured using in situ rat brain perfusion technique.


[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 (PSu) to free drug of (2.63 ± 0.11) × 10−2, (1.60 ± 0.08) × 10−2, and (0.64 ± 0.05) × 10−2 mL s−1 g−1 (n = 9–11), respectively. BBB [14C]ibuprofen uptake was inhibited by unlabeled ibuprofen (K m = 0.85 ± 0.02 mM, V max = 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.


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.

Key Words

blood–brain barrier drug transport plasma protein binding saturable 



blood–brain barrier




perfusion fluid flow


free fraction


transfer constant for unidirectional uptake


half saturation constant


nonsteroidal anti-inflammatory drugs


permeability–surface area product


maximal transport rate of saturable component


vascular volume



This work was supported in part by grant NS052484 from the National Institutes of Health.


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Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Jagan Mohan R. Parepally
    • 1
  • Haritha Mandula
    • 1
  • Quentin R. Smith
    • 1
    Email author
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyTexas Tech University Health Sciences CenterAmarilloUSA

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