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 10 000 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 (kalung) was found to correlate to the apparent permeability (Papp) 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 kalung) from the descriptors log Papp, %PSA and cLog D(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.

[1]  L S Schanker,et al.  Absorption of aerosolized drugs from the rat lung. , 1983, Drug metabolism and disposition: the biological fate of chemicals.

[2]  P. Artursson,et al.  Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. , 1991, Biochemical and biophysical research communications.

[3]  U. Christians,et al.  Active transport of the angiotensin‐II antagonist losartan and its main metabolite EXP 3174 across MDCK‐MDR1 and Caco‐2 cell monolayers , 2000, British journal of pharmacology.

[4]  H Lennernäs,et al.  Human intestinal permeability. , 1998, Journal of pharmaceutical sciences.

[5]  K. Luthman,et al.  Evaluation of dynamic polar molecular surface area as predictor of drug absorption: comparison with other computational and experimental predictors. , 1998, Journal of medicinal chemistry.

[6]  H. Mehendale,et al.  The isolated perfused lung--a critical evaluation. , 1981, Toxicology.

[7]  W. Cefalu,et al.  Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomised proof-of-concept study , 2001, The Lancet.

[8]  J. Patton,et al.  Mechanisms of macromolecule absorption by the lungs , 1996 .

[9]  R A Morrison,et al.  Current methodologies used for evaluation of intestinal permeability and absorption. , 2000, Journal of pharmacological and toxicological methods.

[10]  D. Wall,et al.  High levels of exopeptidase activity are present in rat and canine bronchoalveolar lavage fluid , 1993 .

[11]  Marco C. Stehouwer,et al.  Structure-Transport Relationship for the Intestinal Small-Peptide Carrier: Is the Carbonyl Group of the Peptide Bond Relevant for Transport? , 2004, Pharmaceutical Research.

[12]  P. Beaune,et al.  Expression and localization of CYP3A4 and CYP3A5 in human lung. , 1997, American journal of respiratory cell and molecular biology.

[13]  R. Vestal,et al.  Uptake of propranolol by the lung and its displacement by other drugs: involvement of the alveolar macrophage. , 1980, Pharmacology.

[14]  D. Hipfner,et al.  Immunohistochemical detection of multidrug resistance protein in human lung cancer and normal lung. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[15]  B. Waldeck,et al.  Formoterol and salmeterol are both long acting compared to terbutaline in the isolated perfused and ventilated guinea-pig lung. , 1994, European journal of pharmacology.

[16]  S. Akiyama,et al.  Lung resistance protein (LRP) expression in human normal tissues in comparison with that of MDR1 and MRP. , 1997, Cancer letters.

[17]  H. Möllmann,et al.  Evaluation of pulmonary absorption using pharmacokinetic methods. , 2001, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[18]  D. Wall,et al.  Permeability Characteristics of Calu-3 Human Bronchial Epithelial Cells: In Vitro - In Vivo Correlation to Predict Lung Absorption in Rats , 2002, Journal of drug targeting.

[19]  H. Lennernäs,et al.  Miniaturized nebulization catheters: a new approach for delivery of defined aerosol doses to the rat lung. , 2002, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[20]  A. Clark,et al.  An isolated perfused rat lung preparation for the study of aerosolized drug deposition and absorption. , 1986, Journal of pharmaceutical sciences.

[21]  L S Schanker,et al.  Species comparison of drug absorption from the lung after aerosol inhalation or intratracheal injection. , 1986, Drug metabolism and disposition: the biological fate of chemicals.

[22]  C T Dollery,et al.  CONCENTRATION OF (±)‐PROPRANOLOL IN ISOLATED, PERFUSED LUNGS OF RAT , 1976, British journal of pharmacology.

[23]  P J Sinko.  Drug selection in early drug development: screening for acceptable pharmacokinetic properties using combined in vitro and computational approaches. , 1999, Current opinion in drug discovery & development.

[24]  William J Egan,et al.  Prediction of intestinal permeability. , 2002, Advanced drug delivery reviews.

[25]  A. Ryrfeldt,et al.  Pulmonary disposition of the potent glucocorticoid budesonide, evaluated in an isolated perfused rat lung model. , 1989, Biochemical pharmacology.

[26]  H. Lennernäs,et al.  High airway-to-blood transport of an opioid tetrapeptide in the isolated rat lung after aerosol delivery , 2002, Peptides.

[27]  N. Bodin,et al.  Tissue distribution of metoprolol-(3-h) in the mouse and the rat. , 2009, Acta pharmacologica et toxicologica.

[28]  J. Karlsson,et al.  Tracheobronchial microvessels perfused via the pulmonary artery in guinea-pig isolated lungs. , 1987, Acta physiologica Scandinavica.

[29]  Hans Lennernäs,et al.  Regional differences in bioavailability of an opioid tetrapeptide in vivo in rats after administration to the respiratory tract , 2002, Peptides.

[30]  S. Khor,et al.  Intratracheal Administration of Recombinant Human Factor IX (BeneFix™) Achieves Therapeutic Levels in Hemophilia B Dogs , 2001, Thrombosis and Haemostasis.

[31]  L S Schanker,et al.  Relation between molecular weight and pulmonary absorption rate of lipid-insoluble compounds in neonatal and adult rats. , 1983, Biochemical pharmacology.

[32]  C. Johansson,et al.  Pharmacokinetics of budesonide and its major ester metabolite after inhalation and intravenous administration of budesonide in the rat. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[33]  S. Vožeh.  Pharmacokinetics of inhaled drugs. , 1997, British journal of clinical pharmacology.

[34]  Glyn Taylor,et al.  The absorption and metabolism of xenobiotics in the lung , 1990 .

[35]  D. Groneberg,et al.  Localization of the peptide transporter PEPT2 in the lung: implications for pulmonary oligopeptide uptake. , 2001, The American journal of pathology.

[36]  J. Lötvall,et al.  Relative systemic dose potency and tolerability of inhaled formoterol and salbutamol in healthy subjects and asthmatics , 2000, European Journal of Clinical Pharmacology.

[37]  H Lennernäs,et al.  Correlation of human jejunal permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate data analysis approach. , 1998, Journal of medicinal chemistry.

[38]  M. Hashida,et al.  Effects of various absorption promoters on pulmonary absorption of drugs with different molecular weights. , 1993, Biological & pharmaceutical bulletin.

[39]  Ann Tronde.  Pulmonary Drug Absorption : In vitro and in vivo investigations of drug absorption across the lung barrier and its relation to drug physicochemical properties , 2002 .

[40]  G. Hochhaus,et al.  Methods used to assess pulmonary deposition and absorption of drugs. , 2001, Drug discovery today.