Dynamic Analysis of Fluid Distribution in the Gastrointestinal Tract in Rats: Positron Emission Tomography Imaging after Oral Administration of Nonabsorbable Marker, [18F]Deoxyfluoropoly(et

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• 作者：Tadayuki Takashima ; Tomotaka Shingaki ; Yumiko Katayama ; Emi Hayashinaka ; Yasuhiro Wada ; Makoto Kataoka ; Daiki Ozaki ; Hisashi Doi ; Masaaki Suzuki ; Sho Ishida ; Kentaro Hatanaka ; Yuichi Sugiyama ; Shuji Akai ; Naoto Oku ; Shinji Yamashita ; Yasuyoshi Watanabe
• 刊名：Molecular Pharmaceutics
• 出版年：2013
• 出版时间：June 3, 2013
• 年：2013
• 卷：10
• 期：6
• 页码：2261-2269
• 全文大小：365K
• 年卷期：v.10,no.6(June 3, 2013)
• ISSN：1543-8392

文摘

To develop potent drugs for oral use, information on their pharmacokinetic (PK) properties after oral administration is of great importance. We have recently reported the utility of positron emission tomography (PET) for the analysis of gastrointestinal (GI) absorption of radiolabeled compounds. In this study, PET image analysis was performed in rats using a novel PET probe, [¹⁸F]deoxyfluoropoly(ethylene glycol)s, with an average molecular weight of 2 kDa ([¹⁸F]FPEG), as a nonabsorbable marker to elaborate the GI physiology in more detail, such as segmental transition of the administered water, and fluid volume and distribution in the intestine. After oral administration of [¹⁸F]FPEG solution to rats, a 90 min PET scan with continuous blood sampling was performed, and then the disposition of radioactivity in each part of GI tract was investigated. From blood PK analysis, it was confirmed that the bioavailability of [¹⁸F]FPEG was quite low in rats. PET image analysis showed that the radioactivity after oral administration of [¹⁸F]FPEG solution rapidly passed through the stomach, spread into the proximal small intestine, and then transited toward the distal region of the small intestine without decreasing the radioactivity during GI transition. Radiometabolite analysis revealed that the radioactivity in intestinal mucosal tissues, blood, and urine was mainly derived from unchanged [¹⁸F]FPEG. It was also found that the volume of interest (VOI) after oral administration of the radiotracer enables an understanding of the time-dependent manner of effective fluid volume changes in the stomach and the small intestine. In addition, the rate constant of the intestinal transition of radioactivity in each intestinal segment was calculated by kinetic model analysis, which revealed that PET analysis enables us to determine the GI transit from the same individuals and that it is applicable to determine site-specific intestinal absorption. In conclusion, we demonstrated the high potency of PET imaging technique to elucidate the distribution of orally administered solution in the GI tract in vivo.

Keywords:

oral absorption; positron emission tomography (PET); deoxyfluoropoly(ethylene glycol)s (FPEG); gastrointestinal transit; effective fluid volume