title: Arachidonic acid with taurine enhances pulmonary absorption of macromolecules without any serious histopathological damages.
abstract: Therapeutic peptides and protein are being used in several indications; however, their poor permeability still remains to be solved. This study focused on the pulmonary route of macromolecules. First, the effects of arachidonic acid (AA) as an absorption enhancer on drug serum concentration, after intratracheal administration, were investigated in rats. Second, the safety of AA was assessed in rats in an acute toxicity study for 7days. AA enhanced the exposure of both interferon-α (IFN-α) and fluorescein isothiocyanate 4000 (FD-4). In addition, the histopathological analysis indicated that AA caused alveolitis and bronchitis in rats. In combination with Taurine (Tau), these lung injuries were prevented through the histopathological analysis. The combined use of Tau with AA did not show any changes in the pharmacokinetics of FD-4. From these results, we suggest the combined use of AA with Tau as a novel formulation on the pulmonary route of macromolecule drugs. This formulation could improve the bioavailability of macromolecule drugs without any serious local damage to the lungs.
authors.affiliation: BA Project, Formulation Research Institute, Otsuka Pharmaceutical Co. Ltd., 224-18 Ebisuno Hiraishi Kawauchi-cho, Tokushima 771-0182, Japan. Electronic address: miyake.masateru@otsuka.jp.
authors.forename: Masateru
authors.initials: M
authors.lastname: Miyake
authors.affiliation: Histopathology Research Office, Department of Toxicology, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Minami
authors.affiliation: BA Project, Formulation Research Institute, Otsuka Pharmaceutical Co. Ltd., 224-18 Ebisuno Hiraishi Kawauchi-cho, Tokushima 771-0182, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Department of Drug Metabolism, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co. Ltd., 460-10 Kagasuno Kawauchi-cho, Tokushima 771-0192, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Emoto
authors.affiliation: BA Project, Formulation Research Institute, Otsuka Pharmaceutical Co. Ltd., 224-18 Ebisuno Hiraishi Kawauchi-cho, Tokushima 771-0182, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Mukai
authors.affiliation: BA Project, Formulation Research Institute, Otsuka Pharmaceutical Co. Ltd., 224-18 Ebisuno Hiraishi Kawauchi-cho, Tokushima 771-0182, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Toguchi
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology* / Q000633:toxicity; D019540:Area Under Curve; D001682:Biological Availability; D001991:Bronchitis / Q000139:chemically induced / Q000473:pathology; D004339:Drug Compounding; D016650:Fluorescein-5-isothiocyanate / Q000493:pharmacokinetics; D016898:Interferon-alpha / Q000493:pharmacokinetics; D008168:Lung / Q000187:drug effects* / Q000378:metabolism*; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control; D046911:Macromolecular Substances / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D065589:Respiratory Tract Absorption / Q000187:drug effects*; D013654:Taurine / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D016898:Interferon-alpha; D046911:Macromolecular Substances; D013654:Taurine; D016718:Arachidonic Acid; D016650:Fluorescein-5-isothiocyanate
keywords: Absorption enhancer; Arachidonic acid; Cytoprotection; Histopathology; Local toxicity; Taurine