Pharmaceutical Research

, Volume 23, Issue 5, pp 873–881

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

  • Jagan Mohan R. Parepally
  • Haritha Mandula
  • Quentin R. Smith
Research Paper

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 (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 (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.

Key Words

blood–brain barrier drug transport plasma protein binding saturable 

Abbreviations

BBB

blood–brain barrier

COX

cyclooxygenase

F

perfusion fluid flow

fu

free fraction

Kin

transfer constant for unidirectional uptake

Km

half saturation constant

NSAIDs

nonsteroidal anti-inflammatory drugs

PSu

permeability–surface area product

Vmax

maximal transport rate of saturable component

Vv

vascular volume

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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
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyTexas Tech University Health Sciences CenterAmarilloUSA

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