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

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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 (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.

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.

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Abbreviations

BBB:

blood–brain barrier

COX:

cyclooxygenase

F :

perfusion fluid flow

f u :

free fraction

K in :

transfer constant for unidirectional uptake

K m :

half saturation constant

NSAIDs:

nonsteroidal anti-inflammatory drugs

PSu :

permeability–surface area product

V max :

maximal transport rate of saturable component

V v :

vascular volume

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Acknowledgment

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

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter, Amarillo, Texas, 79106, USA

    Jagan Mohan R. Parepally, Haritha Mandula & Quentin R. Smith

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  1. Jagan Mohan R. Parepally
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  2. Haritha Mandula
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  3. Quentin R. Smith
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Correspondence to Quentin R. Smith.

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Parepally, J.M.R., Mandula, H. & Smith, Q.R. Brain Uptake of Nonsteroidal Anti-Inflammatory Drugs: Ibuprofen, Flurbiprofen, and Indomethacin. Pharm Res 23, 873–881 (2006). https://doi.org/10.1007/s11095-006-9905-5

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