title: Influence of 24-Nor-Ursodeoxycholic Acid on Hepatic Disposition of [(18)F]Ciprofloxacin, a Positron Emission Tomography Study in Mice.
abstract: 24-nor-ursodeoxycholic acid (norUDCA) is a novel therapeutic approach to cholestatic liver diseases. In mouse models of cholestasis, norUDCA induces basolateral multidrug resistance-associated proteins 4 (Mrp4) and 3 in hepatocytes, which provide alternative escape routes for bile acids accumulating during cholestasis but could also result in altered hepatic disposition of concomitantly administered substrate drugs. We used positron emission tomography imaging to study the influence of norUDCA on hepatic disposition of the model Mrp4 substrate [(18)F]ciprofloxacin in wild-type and Mdr2((-/-)) mice, a model of cholestasis. Animals underwent [(18)F]ciprofloxacin positron emission tomography at baseline and after norUDCA treatment. After norUDCA treatment, liver-to-blood area under the curve ratio of [(18)F]ciprofloxacin was significantly decreased compared to baseline, both in wild-type (-34.0 ± 2.1%) and Mdr2((-/-)) mice (-20.5 ± 6.0%). [(18)F]Ciprofloxacin uptake clearance from blood into liver was reduced by -17.1 ± 9.0% in wild-type and by -20.1 ± 7.3% in Mdr2((-/-)) mice. Real-time PCR analysis showed significant increases in hepatic Mrp4 and multidrug resistance-associated protein 3 mRNA after norUDCA. Transport experiments in organic anion transporting polypeptide (OATP)1B1-, OATP1B3-, and OATP2B1-transfected cells revealed weak transport of [(14)C]ciprofloxacin by OATP1B3 and OATP2B1 and no inhibition by norUDCA. In conclusion, our data suggest that changes in hepatic [(18)F]ciprofloxacin disposition in mice after norUDCA treatment were caused by induction of basolateral Mrp4 in hepatocytes.
authors: Biomedical Systems, Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
authors: Thomas
authors: T
authors: Wanek
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors: Emina
authors: E
authors: Halilbasic
authors: Department of Clinical Pharmacology and Toxicology, University Hospital, Zurich, Switzerland.
authors: Michele
authors: M
authors: Visentin
authors: Biomedical Systems, Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
authors: Severin
authors: S
authors: Mairinger
authors: Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Center for Systems Neuroscience, Hannover, Germany.
authors: Kerstin
authors: K
authors: Römermann
authors: Department of Clinical Pharmacology and Toxicology, University Hospital, Zurich, Switzerland.
authors: Bruno
authors: B
authors: Stieger
authors: Biomedical Systems, Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
authors: Claudia
authors: C
authors: Kuntner
authors: Department of Clinical Pharmacology, Medical University of Vienna, Austria.
authors: Markus
authors: M
authors: Müller
authors: Biomedical Systems, Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Austria. Electronic address: oliver.langer@ait.ac.at.
authors: Oliver
authors: O
authors: Langer
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address: michael.trauner@meduniwien.ac.at.
authors: Michael
authors: M
authors: Trauner
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D002779:Cholestasis / Q000188:drug therapy* / Q000378:metabolism; D002939:Ciprofloxacin / Q000097:blood / Q000493:pharmacokinetics*; D003412:Cricetulus; D004195:Disease Models, Animal; D005260:Female; D005462:Fluorine Radioisotopes; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism*; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009928:Organ Specificity; D049268:Positron-Emission Tomography; D013379:Substrate Specificity; D014018:Tissue Distribution; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D002939:Ciprofloxacin; D005462:Fluorine Radioisotopes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014580:Ursodeoxycholic Acid; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C489540:Abcc4 protein, mouse; C081331:24-norursodeoxycholic acid
keywords: ABC transporters; PET; drug interactions; hepatic transport; hepatobiliary disposition; multidrug resistance–associated proteins; organic anion-transporting polypeptide transporters