Abstract
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.
Footnotes
-
This study was supported by grants from the Food and Drug Administration (FD-R-001185), National Institutes of Health (P30 DK27651 and M01 RR-00080), and the Cystic Fibrosis Foundation.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
DOI: 10.1124/jpet.103.052449.
-
ABBREVIATIONS: CF, cystic fibrosis; PMN, neutrophil; NSAID, nonsteroidal anti-inflammatory drug; AUC, area under the plasma concentration-time curve.
- Received April 5, 2003.
- Accepted June 2, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|