Brain Uptake of Nonsteroidal Anti-Inflammatory Drugs: Ibuprofen, Flurbiprofen, and Indomethacin |
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Authors: | Jagan Mohan R Parepally Haritha Mandula Quentin R Smith |
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Institution: | (1) Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter, Amarillo, Texas 79106, USA |
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Abstract: | 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. |
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Keywords: | blood– brain barrier drug transport plasma protein binding saturable |
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