Brain Uptake of Nonsteroidal Anti-Inflammatory Drugs: Ibuprofen, Flurbiprofen, and Indomethacin
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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 Wordsblood–brain barrier drug transport plasma protein binding saturable
perfusion fluid flow
transfer constant for unidirectional uptake
half saturation constant
nonsteroidal anti-inflammatory drugs
permeability–surface area product
maximal transport rate of saturable component
This work was supported in part by grant NS052484 from the National Institutes of Health.
- 7.Matoga, M., Pehourcq, F., Lagrange, F., Tramu, G., Bannwarth, B. 1999Influence of molecular lipophilicity on the diffusion of arylpropionate non-steroidal anti-inflammatory drugs into the cerebrospinal fluidArzneim.-Forsch.49477482Google Scholar
- 13.Nozaki, Y., Kusuhara, H., Endou, H., Sugiyama, Y. 2004Quantitative evaluation of the drug–drug interactions between methotrexate and nonsteroidal anti-inflammatory drugs in the renal uptake process based on the contribution of organic anion transporters and reduced folate carrierJ. Pharmacol. Exp. Ther.309226234PubMedCrossRefGoogle Scholar
- 20.Peters, T. J. 1996All About AlbuminAcademic Press, Inc.San Diego, CAGoogle Scholar
- 25.Ohtsuki, S., Kikkawa, T., Mori, S., Hori, S., Takanaga, H., Otagiri, M., Terasaki, T. 2004Mouse reduced in osteosclerosis transporter functions as an organic anion transporter 3 and is localized at abluminal membrane of blood–brain barrierJ. Pharmacol. Exp. Ther.30912731281PubMedCrossRefGoogle Scholar
- 29.Ohtsuki, S., Takizawa, T., Takanaga, H., Terasaki, N., Kitazawa, T., Sasaki, M., Abe, T., Hosoya, K., Terasaki, T. 2003 In vitro study of the functional expression of organic anion transporting polypeptide 3 at rat choroid plexus epithelial cells and its involvement in the cerebrospinal fluid-to-blood transport of estrone-3-sulfateMol. Pharmacol.63532537PubMedCrossRefGoogle Scholar
- 32.Pardridge, W. M. 1998Targeted delivery of hormones to tissues by plasma proteinsconn, P. M. eds. Handbook of Physiology Section 7: The Endocrine SystemOxford University PressNew York335382Google Scholar
- 35.Deguchi, Y., Hayashi, H., Fujii, S., Naito, T., Yokoyama, Y., Yamada, S., Kimura, R. 2000Improved brain delivery of a nonsteroidal anti-inflammatory drug with a synthetic glyceride ester: a preliminary attempt at a CNS drug delivery system for the therapy of Alzheimer's diseaseJ. Drug Target8371381PubMedCrossRefGoogle Scholar