title: In vivo evaluation of supersaturation/precipitation/re-dissolution behavior of cinnarizine, a lipophilic weak base, in the gastrointestinal tract: the key process of oral absorption.
abstract: The aim of this study is to evaluate how supersaturation, precipitation, and re-dissolution processes influence the intestinal absorption of cinnarizine (CNZ), a lipophilic weak base, by monitoring its plasma and luminal concentration-time profile, after oral administration as a HCl solution containing fluorescein isothiocyanate dextran (FD-4), a non-absorbable marker. In the in vitro pH shift experiment, the supersaturation stability was significantly lower when the higher-concentration solution of CNZ (pH1.5) was added to the simulated intestinal fluid. However, although the in vivo bioavailability after oral administration of high and low dose as HCl solutions was greatly improved compared to those as neutral suspensions, the difference in the supersaturation stability was not reflected in the improvement of the in vivo bioavailability. Analysis of CNZ and FD-4 concentrations in each segment of the gastrointestinal tract revealed that most of the CNZ precipitated in the duodenum after gastric emptying, and supersaturation was observed only in the duodenum. Thereafter, the precipitate was rapidly re-dissolved and absorbed in the upper and middle small intestine. The rapid re-dissolution may be caused by smaller particles of the precipitate. In this case, it is considered that the key process for the absorption of CNZ was re-dissolution, not supersaturation. Therefore, different supersaturation stabilities in different doses observed in in vitro precipitation experiment was not reflected to in vivo absorption. These findings may be useful to design efficient supersaturable formulations and to validate and improve current prediction methods.
authors: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan. Electronic address: y-tanaka@ps.hirokoku-u.ac.jp.
authors: Yusuke
authors: Y
authors: Tanaka
authors: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
authors: Ayaka
authors: A
authors: Kawakami
authors: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
authors: Ami
authors: A
authors: Nanimatsu
authors: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
authors: Misaki
authors: M
authors: Horio
authors: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
authors: Jumpei
authors: J
authors: Matsuoka
authors: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
authors: Takami
authors: T
authors: Wada
authors: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
authors: Satoshi
authors: S
authors: Kasaoka
authors: Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
authors: Hiroshi
authors: H
authors: Yoshikawa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D011232:Chemical Precipitation; D002936:Cinnarizine / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism*; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility / Q000187:drug effects
chemical_list: D002936:Cinnarizine
keywords: Lipophilic weak base; Luminal concentration; Re-dissolution; Supersaturation