title: The involvement of organic anion transporting polypeptide in the hepatic uptake of telmisartan in rats: PET studies with [¹¹C]telmisartan.
abstract: Telmisartan, a selective angiotensin II receptor antagonist, is primarily excreted via hepatobiliary transport. The predominant contribution of organic anion transporting polypeptide (OATP) 1B3 in its hepatic uptake of telmisartan has been demonstrated by in vitro transport studies. In the present study, a quantitative positron emission tomography (PET) methodology was developed for in vivo kinetic assessment of hepatobiliary transport of telmisartan. Serial abdominal PET scans were performed in rats following intravenous administration of [(11)C]telmisartan as a radiotracer. PET scans revealed that [(11)C]telmisartan was localized primarily in the liver and some of the radioactivity moved to the intestine, which corresponds to biliary excretion. Radiometabolite analysis by radiometric HPLC showed that [(11)C]telmisartan was converted to its acylglucuronide, which was mainly detected in bile, but little in plasma and liver. Integration plot analysis revealed that [(11)C]telmisartan was taken up into the liver as rapidly as the hepatic blood flow rate, and the radiometabolite was subsequently excreted into the bile. When rifampicin, a typical Oatp inhibitor, was coadministered with [(11)C]telmisartan in rats, hepatic uptake clearance of [(11)C]telmisartan was significantly decreased, whereas biliary efflux clearance was not changed. Coinjection with unlabeled telmisartan (4 and 10 mg/kg) also decreased hepatic uptake clearance of [(11)C]telmisartan. On the other hand, PET imaging analysis revealed a significant increase of biliary efflux when telmisartan dose was increased to more than 4 mg/kg. These results suggested that the hepatic uptake of [(11)C]telmisartan mainly consists of a saturable process mediated by Oatps in rats, according to noninvasive real-time measurement of tissue radioactivity with the use of PET. The present study with rats is expected to provide the feasibility of PET imaging study to quantitatively estimate OATP1B3 function in humans.
authors.affiliation: RIKEN Center for Molecular Imaging Science, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. ttakashima@riken.jp
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Takashima
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Hashizume
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Katayama
authors.forename: Machiko
authors.initials: M
authors.lastname: Murai
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Wada
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Watanabe
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D001565:Benzoates / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D001646:Bile / Q000737:chemistry; D001692:Biological Transport / Q000187:drug effects; D001711:Biotransformation / Q000187:drug effects; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005240:Feasibility Studies; D008099:Liver / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D008102:Liver Circulation; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049268:Positron-Emission Tomography; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000494:pharmacology; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000077333:Telmisartan; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D029362:Organic Anion Transporters, Sodium-Independent; D020033:Protein Isoforms; C421207:Slco1b2 protein, rat; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000077333:Telmisartan; D012293:Rifampin