title: Novel in vivo imaging analysis of an inner ear drug delivery system: Drug availability in inner ear following different dose of systemic drug injections.
abstract: Systemic application of drugs is commonly used in clinical situations. Some of these drugs are ototoxic. Since there are few studies on in vivo monitoring of drug delivery dynamics, the time course or bioavailability of drugs in the inner ear of live animals following systemic drug application remains unknown. For instance, it is unknown whether the volume of a drug delivered systemically correlates with its inner ear pharmacokinetics. We previously established a new in vivo imaging system to monitor drug delivery in live mice. In the present study, we used this system to compare drug concentration in the inner ear over time after systemic drug injections. We used transgenic GFAP-Luc mice that harbor a firefly luciferase gene expression cassette regulated by 12 kb of murine GFAP promoter and human beta-globin intron 2. Luciferin delivered into the inner ear of these mice reacts with luciferase, and the resulting signals are detected in GFAP-expressing cells in the cochlear nerve. Thus, we assessed in the inner ear the intensity and duration of luciferin/luciferase signals after systemic injections of different volumes of luciferin. An IVIS(®) imaging system was used to observe signals, and these signals were compared to the drug dynamics of luciferin delivered through subcutaneous (sc) injections. The volume of sc-injected drug correlated significantly with photon counts measured in the inner ear. Photons were detected almost immediately after injection, peaking 20 min after injection. Drug concentration did not affect inner ear signals. Luciferin injected systemically appeared in the inner ear between highest and lowest concentration. Drug volume is an important parameter to know if the inner ear requires a higher level of the drug. We observed that it is the volume of a drug-not its concentration-that is the important factor. Indeed, the more volume of a drug injected systemically increased the concentration of that drug in the inner ear. This study provides a better understanding of in vivo drug delivery dynamics measured in the inner ear. Further studies will show whether a high dosage of drug is effective or not.
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: skan@a7.keio.jp.
authors.forename: Sho
authors.initials: S
authors.lastname: Kanzaki
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Fujioka
authors.affiliation: Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Department of Orthopedics, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Division of Regenerative Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Hirotaka James
authors.initials: HJ
authors.lastname: Okano
authors.affiliation: Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D019540:Area Under Curve; D003051:Cochlea / Q000502:physiology; D016503:Drug Delivery Systems; D007758:Ear, Inner / Q000187:drug effects*; D049454:Firefly Luciferin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D006801:Humans; D007279:Injections, Subcutaneous; D007438:Introns; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D055544:beta-Globins / Q000235:genetics
chemical_list: D005904:Glial Fibrillary Acidic Protein; D055544:beta-Globins; C528900:glial fibrillary astrocytic protein, mouse; D049454:Firefly Luciferin; D008156:Luciferases
keywords: Bioluminescence imaging; Drug delivery system; Inner ear; Mouse