Drug absorption from the isolated perfused rat lung--correlations with drug physicochemical properties and epithelial permeability.
The pulmonary absorption of nine low-molecular-weight (225-430 Da) drugs (atenolol, budesonide, enalaprilat, enalapril, formoterol, losartan, metoprolol, propranolol and terbutaline) and one high-molecular-weight membrane permeability marker compound (FITC-dextran 10000 Da) was investigated using the isolated, perfused and ventilated rat lung (IPL). The relationships between pulmonary transport characteristics, epithelial permeability of Caco-2 cell monolayers and drug physicochemical properties were evaluated using multivariate data analysis. Finally, an in vitro-in vivo correlation was made using in vivo rat lung absorption data. The absorption half-life of the investigated drugs ranged from 2 to 59 min, and the extent of absorption from 21 to 94% in 2 h in the isolated perfused rat lung model. The apparent first-order absorption rate constant in IPL (ka(lung)) was found to correlate to the apparent permeability (P(app)) of Caco-2 cell monolayers (r = 0.87), cLog D(7.4) (r = 0.70), cLog P, and to the molecular polar surface area (%PSA) (r = -0.79) of the drugs. A Partial Least Squares (PLS)-model for prediction of the absorption rate (log ka(lung)) from the descriptors log P(app), %PSA and cLogD(7.4) was found (Q2 = 0.74, R2 = 0.78). Furthermore, a strong in vitro-in vivo correlation (r = 0.98) was found for the in vitro (IPL) drug absorption half-life and the pulmonary absorption half-life obtained in rats in vivo, based on a sub-set of five compounds.
Tronde
Ann
A
Department of Pharmacy, Uppsala University, Box 580, BMC, SE-751 23 Uppsala, Sweden. ann.tronde@astrazeneca.com
Nordén
Bo
B
Jeppsson
Ann-Britt
AB
Brunmark
Per
P
Nilsson
Elisabeth
E
Lennernäs
Hans
H
Bengtsson
Ursula Hultkvist
UH
D000042:Absorption / Q000502:physiology; D000818:Animals; D018938:Caco-2 Cells; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism*; D008297:Male; D010477:Perfusion / Q000379:methods; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004364:Pharmaceutical Preparations