title: Pulmonary delivery of d-methionine is associated with an increase in ALCAR and glutathione in cochlear fluids.
abstract: In animals, hearing loss resulting from cochlear mechanosensory cell damage can be mitigated by antioxidants such as d-methionine (d-met) and acetyl-l-carnitine (ALCAR). The systemic routes of administration of these compounds, that must of necessity transit trough the cochlear fluids, may affect the antioxidant levels in the cochlea and the resulting oto-protective effect. In this study, we analyzed the pharmacokinetics of [(14)C]d-met in the cochlea and four other tissues after intratracheal (IT), intranasal (IN), and oral by gavage (OG) administration and compared it to intravenous administration (IV). We then analyzed the effect of these four routes on the antioxidant content of the cochlear fluids after d-met or ALCAR administration, by liquid chromatography/mass spectrometry. Our results showed that the concentration of methionine and ALCAR in cochlear fluids significantly increased after their respective systemic administration. Interestingly, d-met administration also contributed to an increase of ALCAR. Our results also showed that the delivery routes differently affected the bioavailability of administered [(14)C]d-met as well as the concentrations of methionine, ALCAR and the ratio of oxidized to reduced glutathione. Overall, pulmonary delivery via IT administration achieved high concentrations of methionine, ALCAR, and oxidative-related metabolites in cochlear fluids, in some cases surpassing IV administration, while IN route appeared to be the least efficacious. To our knowledge, this is the first report of the direct measurements of antioxidant levels in cochlear fluids after their systemic administration. This report also demonstrates the validity of the pulmonary administration of antioxidants and highlights the different contributions of d-met and ALCAR allowing to further investigate their impact on oxidative stress in the cochlear microenvironment.
authors.affiliation: Molecular and Integrative Physiologic Sciences Program, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Grondin
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Cotanche
authors.forename: Otto
authors.initials: O
authors.lastname: Manneberg
authors.forename: Ramon
authors.initials: R
authors.lastname: Molina
authors.forename: J Humberto
authors.initials: JH
authors.lastname: Treviño-Villarreal
authors.forename: Rosalinda
authors.initials: R
authors.lastname: Sepulveda
authors.forename: Royce
authors.initials: R
authors.lastname: Clifford
authors.forename: Magda E
authors.initials: ME
authors.lastname: Bortoni
authors.forename: Scott
authors.initials: S
authors.lastname: Forsberg
authors.forename: Brian
authors.initials: B
authors.lastname: Labrecque
authors.forename: Larisa
authors.initials: L
authors.lastname: Altshul
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Brain
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Jackson
authors.forename: Rick A
authors.initials: RA
authors.lastname: Rogers
mesh_terms: D000108:Acetylcarnitine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000280:Administration, Inhalation; D000281:Administration, Intranasal; D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001682:Biological Availability; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004710:Endolymph / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D007275:Injections, Intravenous; D007761:Labyrinthine Fluids / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008715:Methionine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010498:Perilymph / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000975:Antioxidants; D000108:Acetylcarnitine; D008715:Methionine; D005978:Glutathione