Can xipamide or tacrolimus inhibit the glucuronidation of mycophenolic acid in rat liver slices?
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.
Balogh
Annegret
A
Institute of Clinical Pharmacology, Friedrich Schiller University Jena, Germany. annegret.balogh@med.uni-jena.de
Merkel
Ute
U
Müller
Dieter
D
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*
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