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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 13, 2003; DOI: 10.1124/jpet.103.052449

0022-3565/03/3063-1086-1091$20.00
JPET 306:1086-1091, 2003
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INFLAMMATION AND IMMUNOPHARMACOLOGY

Effect of Ibuprofen on Neutrophil Migration in Vivo in Cystic Fibrosis and Healthy Subjects

Michael W. Konstan, Jeanne E. Krenicky, Marcie R. Finney, H. Lester Kirchner, Kathleen A. Hilliard, Jay B. Hilliard, Pamela B. Davis, and Charles L. Hoppel

Departments of Pediatrics (M.W.K., J.E.K., H.L.K., K.A.H., J.B.H., P.B.D.) and Pharmacology and Medicine (M.R.F., C.L.H.), Case Western Reserve University School of Medicine; Rainbow Babies and Children's Hospital (M.W.K., J.E.K., H.L.K., K.A.H., J.B.H., P.B.D.); and Veterans Affairs Medical Center (M.R.F., C.L.H.), Cleveland, Ohio

Long-term treatment with ibuprofen twice daily, at doses that achieve peak plasma concentration (Cmax) >50 µg/ml, slows progression of lung disease in patients with cystic fibrosis (CF). Previous data suggest that Cmax >50 µg/ml is associated with a reduction in neutrophil (PMN) migration into the lung and that lower concentrations are associated with an increase in PMN migration. To estimate the threshold concentration at which ibuprofen is associated with a decrease in PMN migration in vivo, we measured the PMN content of oral mucosal washes in 35 healthy (age 19-40 years) and 16 CF (age 18-32 years) subjects who took ibuprofen twice daily for 10 days in doses that achieved Cmax 8 to 90 µg/ml. Cmax >50 µg/ml was associated with a 31 ± 7% (mean ± S.E.M.) reduction in PMNs in CF (n = 11, p < 0.001) and 25 ± 6% reduction in PMNs in healthy subjects (n = 16, p < 0.001). Increasing concentrations above 50 µg/ml was not associated with a greater decrease in PMNs. The reduction in PMN migration was consistently present 12 h after a dose, but not after 24 h. Cmax <50 µg/ml was associated with an increase in PMNs of approximately 40%. These results suggest that Cmax >50 µg/ml and twice daily dosing of ibuprofen are required to decrease PMN migration, and reinforce the current recommendation that pharmacokinetics should be performed in CF patients prescribed ibuprofen.

Received April 5, 2003; accepted June 2, 2003.

Address correspondence to: Dr. Michael W. Konstan, Rainbow Babies and Children's Hospital, 11100 Euclid Ave., Cleveland, OH 44106. E-mail: mwk3{at}cwru.edu




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