Dynamic Analysis of GI Absorption and Hepatic Distribution Processes of Telmisartan in Rats Using Positron Emission Tomography

• Published in: Pharmaceutical research 2012-09, Vol.29 (9), p.2419-2431
• Main Authors: Kataoka, Makoto, Takashima, Tadayuki, Shingaki, Tomotaka, Hashidzume, Yoshinobu, Katayama, Yumiko, Wada, Yasuhiro, Oh, Hiroyuki, Masaoka, Yoshie, Sakuma, Shinji, Sugiyama, Yuichi, Yamashita, Shinji, Watanabe, Yasuyoshi
• Format: Article
• Language: English
• Subjects: Animals; Benzimidazoles - pharmacokinetics; Benzoates - pharmacokinetics; Biochemistry; Biological and medical sciences; Biological Availability; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Gastrointestinal Tract - metabolism; General pharmacology; Intestinal Absorption; Liver; Liver - metabolism; Male; Medical Law; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Positron-Emission Tomography - methods; Rats; Rats, Sprague-Dawley; Research Paper; Rodents; Tomography
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-012-0768-7

ABSTRACT Purpose To dynamically analyze the processes of oral absorption and hepatobiliary distribution of telmisartan using positron emission tomography (PET). Methods 11 C-labeled telmisartan ([ 11 C]TEL) was orally administered to rats with or without non-radiolabeled telmisartan (0.5, and 10 mg/kg). PET scanning of abdominal region and whole body was performed under conscious condition. In situ intestinal closed loop study in rats and in vitro permeation study in MDR1-MDCK II cell monolayers were also conducted. Results After oral administration of [ 11 C]TEL, systemic bioavailability and hepatic distribution of radioactivity increased non-linearly with dose. In the intestinal lumen, both telmisartan and its glucuronide were detected and the ratio of telmisartan decreased dramatically at high dose of telmisartan. In situ closed loop study showed most of telmisartan-glucuronide detected in the intestinal lumen was derived from the bile excretion. In addition, in vitro permeation study revealed that telmisartan is a substrate of P-glycoprotein. Conclusion PET imaging analysis successfully demonstrated the processes of intestinal absorption and hepatic distribution of telmisartan. PET study combined with appropriate in situ and in vitro experiments is highly expected to be a potent tool for better understanding of GI absorption and subsequent tissue distribution of various drugs and drug candidates.