title: Can xipamide or tacrolimus inhibit the glucuronidation of mycophenolic acid in rat liver slices?
abstract: The objective of this study was to investigate the effect of tacrolimus (Tac) and xipamide (X) on mycophenolic acid (MPA) glucuronidation in precision-cut rat liver slices. To assess a possible effect of these two drugs, the influence of the anti-inflammatory drug niflumic acid (NA)--a well-known inhibitor for MPA glucuronidation in human liver microsomes--was used as a standard. MPA and its main metabolite mycophenolic acid glucuronide (MPAG) were determined by means of high-performance liquid chromatography. MPA glucuronidation rate showed a significant linear correlation (p = 0.012) with MPA concentrations from 15.61 up to 124.88 microM in the medium. That means, the enzyme(s) responsible for the glucuronidation of MPA worked far below Km-value. With all MPA concentrations tested, neither the addition of Tac (31.30 nM) nor of X (28.25 nM) influenced the glucuronidation of MPA. In comparison, NA at a concentration of 70.92 nM showed a marked inhibitory effect (by 72%). The present pilot-study indicates that precision-cut rat liver slices are a suitable in vitro model to characterize the glucuronidation of MPA to its primary metabolite MPAG and interferences with other substances.
authors.affiliation: Institute of Clinical Pharmacology, Friedrich Schiller University Jena, Germany. annegret.balogh@med.uni-jena.de
authors.forename: Annegret
authors.initials: A
authors.lastname: Balogh
authors.forename: Ute
authors.initials: U
authors.lastname: Merkel
authors.forename: Dieter
authors.initials: D
authors.lastname: Müller
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004232:Diuretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000378:metabolism*; D020719:Glucuronides / Q000037:antagonists & inhibitors; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009173:Mycophenolic Acid / Q000378:metabolism*; D009544:Niflumic Acid / Q000494:pharmacology; D009924:Organ Culture Techniques; D010865:Pilot Projects; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology*; D014988:Xipamide / Q000494:pharmacology*
chemical_list: D004232:Diuretics; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D020719:Glucuronides; D007166:Immunosuppressive Agents; D014988:Xipamide; D009544:Niflumic Acid; D014453:Glucuronosyltransferase; D009173:Mycophenolic Acid; D016559:Tacrolimus