title: Effect of Absorption Behavior of Solubilizers on Drug Dissolution in the Gastrointestinal Tract: Evaluation Based on In Vivo Luminal Concentration-Time Profile of Cilostazol, a Poorly Soluble Drug, and Solubilizers.
abstract: The purpose of this study was to evaluate the effect of absorption behavior of solubilizers on drug dissolution in the gastrointestinal tract. After oral administration of FITC-dextran (FD-10), a nonabsorbable marker, and cilostazol (CZ), a low-solubility drug, with or without solubilizers (dimethyl sulfoxide [DMSO], and d-α-tocopherol polyethylene glycol 1000 succinate [TPGS]), the in vivo rat luminal concentrations of these compounds were determined by direct sampling of residual water in each segment of the gastrointestinal tract. DMSO was rapidly absorbed and not detected in the middle small intestine. Conversely, the TPGS concentration increased by 1.5- and 2-fold relative to the initial dose concentration in the middle and lower small intestine, respectively, owing to condensation. Then, normalized area under the luminal concentration-time curve of solid CZ was calculated from the luminal concentration-time profiles of FD-10 and solid CZ to evaluate in vivo dissolution behavior of CZ. The dissolution of CZ was marked when administered with TPGS compared with that when administered with DMSO, especially in the lower small intestine. This clearly indicates that absorbability of solubilizers is one of the important factors in determining the solubilizing effect. These findings may be beneficial to development of oral lipophilic drugs.
authors.affiliation: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan. Electronic address: y-tanaka@ps.hirokoku-u.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kubota
authors.affiliation: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuo
authors.affiliation: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Kawakami
authors.affiliation: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kamizi
authors.affiliation: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan.
authors.forename: Akane
authors.initials: A
authors.lastname: Mochigoe
authors.affiliation: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hiramachi
authors.affiliation: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kasaoka
authors.affiliation: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshikawa
authors.affiliation: Laboratory of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Nagata
mesh_terms: D000818:Animals; D019540:Area Under Curve; D000077407:Cilostazol; D003911:Dextrans; D004121:Dimethyl Sulfoxide; D005079:Excipients; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D041981:Gastrointestinal Tract / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013777:Tetrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D014810:Vitamin E
chemical_list: D003911:Dextrans; D005079:Excipients; D013777:Tetrazoles; C015219:fluorescein isothiocyanate dextran; D014810:Vitamin E; D016650:Fluorescein-5-isothiocyanate; D000077407:Cilostazol; C014225:tocophersolan; D004121:Dimethyl Sulfoxide
keywords: bioequivalence; dissolution; oral absorption; poorly water-soluble drugs; solubility