Received for publication January 26, 2005.
Revised May 6, 2005.
Accepted for publication May 6, 2005.

Metabolism of verapamil in cultures of rat alveolar epithelial cells and pharmacokinetics after administration by intravenous and inhalation routes

Abstract

Administration of therapeutic entities by inhalation opens new possibilities for drug entry into systemic circulation, but this requires passage through the alveolar epithelium. Little is known about the pulmonary metabolism of verapamil. Specifically, this cardiovascular drug suffers from extensive first pass metabolism. We therefore evaluated the metabolism of verapamil in cultured alveolar epithelium and compared findings with results after administration by inhalation and intravenous (i.v.) routes. Specifically, cell culture of alveolar epithelium was characterised by gene expression of surfactant proteins A, B, C and D, by immunohistochemistry of surfactant protein C, by staining for laminar bodies and by gene expression of CYP monooxygenases. During six days of culture expression of all cellular differentiation markers was obvious, albeit at different levels. With testosterone as substrate we found alveolar epithelial cells to produce several stereo- and site-specific hydroxylation products. This provided evidence for metabolic competence of cultured alveolar epithelial cells. With verapamil as substrate only limited production of metabolites was observed in cell culture assays and similar results were recorded after administration by inhalation and i.v. routes. Likewise, elimination of verapamil from lung tissue and plasma was similar by both routes of administration. In conclusion, administration of verapamil by inhalation abrogated extensive first pass metabolism frequently seen after oral application and this may well be extended to the development of drugs with similar pharmacokinetic defects.

Key words: CYP expression, CYP induction, cytochrome P450 catalyzed oxidations, cytochrome P450 isoforms, inhaled drugs, pharmacokinetics, pulmonary metabolism