title: Characterization of lidocaine metabolism by rat nasal microsomes: implications for nasal drug delivery.
abstract: Lidocaine has been recently approved for use as an intranasal spray in the treatment of migraine. In this study, we investigated the metabolism of lidocaine to its primary metabolite monoethylglycine xylidide (MEGX), by rat nasal olfactory and respiratory microsomes. The metabolic parameters were compared with metabolism employing rat and human hepatic microsomes. The olfactory and respiratory microsomes both exhibited considerable activity for conversion of lidocaine to MEGX in comparison with the activity in the hepatic tissues. The rat olfactory microsomes had a markedly higher affinity than the rat hepatic or respiratory microsomes. However, the turnover rate was only about one-half that of rat liver. Employing Western immunoblotting we investigated the presence of cytochrome P450s (CYPs) 1A2, 3A2, 2B1 and 2C11 in rat nasal tissues; these isozymes are known to partcipated in the metabolism of lidocaine in rat liver. These isozymes were found to be present in significant amounts in both the nasal olfactory and respiratory tissue; this is the first known report of the presence of CYP2C11 in nasal mucosae. Our studies underscore the importance of CYP-mediated drug metabolism in nasal tissues. The effect of this 'nasal first-pass' should be weighed carefully while considering the fate and the bioavailability of drugs delivered via the intranasal route.
authors.affiliation: Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Ohio 45267-0004, USA.
authors.forename: V S
authors.initials: VS
authors.lastname: Deshpande
authors.forename: M B
authors.initials: MB
authors.lastname: Genter
authors.forename: C
authors.initials: C
authors.lastname: Jung
authors.forename: P B
authors.initials: PB
authors.lastname: Desai
mesh_terms: D000779:Anesthetics, Local / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000145:classification; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008012:Lidocaine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D009297:Nasal Mucosa / Q000378:metabolism*; D009831:Olfactory Mucosa / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D000779:Anesthetics, Local; D003577:Cytochrome P-450 Enzyme System; D008012:Lidocaine; C001173:monoethylglycinexylidide