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Uptake and P‐glycoprotein (P‐gp) mediated efflux of four rhodamine dyes in the intact rat lung
Author(s) -
Roerig David,
Ahlf Susan,
Audi Said
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1143-a
Subject(s) - efflux , rhodamine 123 , chemistry , lipophilicity , rhodamine , chromatography , rhodamine 6g , fluorescence , pharmacology , biochemistry , biophysics , organic chemistry , medicine , biology , multiple drug resistance , physics , quantum mechanics , antibiotics , molecule
A functional multidrug efflux transporter (P‐gp) has been demonstrated in the rat intact lung that has a significant effect on limiting the pulmonary accumulation of the rhodamine 6G dye (R6G) (1). In the present study we compared the contribution of P‐gp mediated efflux to the pulmonary disposition of four structurally related rhodamine dyes R6G, tetramethylrhodamine ethyl ester (TMRE), tetramethylrosamine (TMR) and rhodamine 123 (R123). These dyes differ primarily in their lipophilicity. Each dye (0.25M in artificial perfusate) was infused (10 ml/min) into an isolated perfused rat lung for 6 min and the instantaneous dye extraction determined from their conc. in timed venous effluent fractions. The four rhodamine dyes exhibited a wide range of extractions by the intact lung. At the 6 min time point the extractions for TMR, R6G, TMRE and R123 were 0.70±.03, 0.46±.02, 0.26±.05 and 0.023±.015 respectively. The extraction of these dyes was also determined in isolated rat lungs in the presence of the specific P‐gp efflux inhibitor GF120918. This resulted in a significant increase in the pulmonary extractions of TMR, R6G, TMRE but not R123 which were 0.88± .02, 0.68±.01, 0.45±.01 and 0.025±.02 respectively. Based on their extent of uptake and the effect of P‐gp inhibition the fluorescent rhodamine dyes TMR, R6G and TMRE are useable substrates for examining the role of P‐gp mediated drug efflux in pulmonary drug disposition in the intact lung. (1) Roerig et al, FASEB J 19:A543, 2005. Supported by Dept of Veterans Affairs, NHLBI HL 24349.