Pulmonary absorption rate and bioavailability of drugs in vivo in rats: structure-absorption relationships and physicochemical profiling of inhaled drugs.

The aim of this investigation was to analyze the structure-absorption relationships for pulmonary delivered drugs. First, the inhaled drugs on the market during 2001 were identified and a profile of the calculated physicochemical properties was made. Second, an in vivo pharmacokinetic investigation was performed in anesthetized rats. Eight selected drugs were administered by intratracheal nebulization and intravenous bolus administration and the plasma concentrations of the drugs were determined by LC-MS-MS. Third, an evaluation of the relationships between the absorption/bioavailability data and the drugs' physicochemical characteristics and the epithelial permeability in Caco-2 cells, respectively, was performed. The drug absorption rate was found to correlate to the molecular polar surface area and the hydrogen bonding potential, as well as to the apparent permeability in Caco-2 cell monolayers, which indicated that passive diffusion was the predominating mechanism of absorption in the rat lung. In contrast to the intestinal mucosa and the blood-brain barrier, the pulmonary epithelium was shown to be highly permeable to compounds with high molecular polar surface area (e.g., PSA 479 A(2)). Furthermore, a high bioavailability was found for the efflux transporter substrates talinolol (81%) and losartan (92%), which provides functional evidence for a quantitatively less important role for efflux transporters, such as P-glycoprotein, in limiting the absorption of these drugs from the rat lung. In conclusion, the pulmonary route should be regarded as a potential alternative for the delivery of drugs that are inadequately absorbed after oral administration. Copyright 2003 Wiley-Liss, Inc.