Extrahepatic sites of metabolism of halothane in the rat

Rats were given 14C-halothane intravenously and whole-body autoradiography with freeze-dried sections, or with sections extracted in trichloroacetic acid, water, and organic solvents, was carried out to trace tissues accumulating halothane metabolites. In vitro incubations of tissue homogenates were performed to examine the capacity by the various organs to form tissue-bound 14C from the 14C-halothane. Autoradiography of isolated organs after incubation with 14C-halothane was performed to study the tissue localization of halothane metabolites formed under in vitro conditions. A localization of halothane metabolites was observed in several extrahepatic tissues in vivo, and the in vitro experiments showed a capacity by the same tissues to transform 14C-halothane to metabolites that bind strongly to tissue components. In addition to the liver, the other tissues shown to have a marked halothane-metabolizing capacity were the nasal mucosa, lateral nasal gland, mucosa of the tongue, cheek, soft palate (but not the hard palate), pharynx, larynx, oesophagus, and the tracheo-bronchial mucosa. The in vivo data obtained indicated a diffusion of the halothane over the walls of the large intestine and the caecum, followed by the formation of apparently reductive metabolites by intestinal microbes and a binding of the metabolites to the intestinal contents. The localization of halothane metabolites in the upper alimentary and respiratory pathways is correlated to the presence of cytochrome P-450 at these sites.