title: Glucuronidation and subsequent biliary excretion of mycophenolic acid in rat sandwich-cultured hepatocytes.
abstract: Rat sandwich-cultured hepatocytes (SCH) were used to correlate the in vitro hepatic disposition of mycophenolic acid (MPA) with published in vivo data, as well as mechanistic studies on drug-drug interaction. The major metabolite of MPA in SCH was 7-O-glucuronide (MPAG) followed by acyl-glucuronide (AcMPAG). MPAG and AcMPAG, but not MPA, showed significant in vitro biliary excretion with biliary excretion indexes (BEI) of 40% for MPAG and 45% for AcMPAG. While these BEIs were similar, the biliary excretion amount (BEA) of MPAG (120 pmol/mg protein) was orders of magnitude higher than that of AcMPAG (0.34 pmol/mg protein). Since MPAG is the major metabolite in in vivo bile, we propose that BEA is a better qualifier of biliary excretion. Quercetin inhibited MPAG and AcMPAG production, while chrysin inhibited only MPAG production, showing that chrysin is not a pan-glucuronidation inhibitor. Cyclosporin A (CysA) reduced the BEI of MPAG and increased intracellular MPA accumulation without changing MPAG amounts. These results suggest that CysA causes inhibition of biliary excretion of MPAG, as well as a mixed inhibition of glucuronidation of MPA and sinusoidal efflux of MPA/MPAG. In conclusion, the present study demonstrates a good agreement of hepatic MPA disposition between SCH and in vivo rats.
authors.affiliation: Astellas Research Institute of America LLC.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tetsuka
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gerst
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tamura
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Masters
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004347:Drug Interactions; D005419:Flavonoids / Q000494:pharmacology; D020719:Glucuronides / Q000378:metabolism*; D065669:Hepatobiliary Elimination / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000378:metabolism*; D061251:Primary Cell Culture; D011794:Quercetin / Q000494:pharmacology; D017207:Rats, Sprague-Dawley
chemical_list: D005419:Flavonoids; D020719:Glucuronides; D007166:Immunosuppressive Agents; C043561:chrysin; D016572:Cyclosporine; D011794:Quercetin; D009173:Mycophenolic Acid