title: Influence of cyclosporine on the serum concentration and biliary excretion of mycophenolic acid and 7-O-mycophenolic acid glucuronide.
abstract: The authors have investigated whether cyclosporine decreases the serum concentration of mycophenolic acid, the active principle of the immunosuppressant mycophenolate mofetil, and increases that of the inactive metabolite 7-O-mycophenolic acid glucuronide by reducing their enterohepatic recirculation. Rats were treated daily with methylcellulose (1.66 mL/kg PO) plus 0.9% NaCl (6 mL/kg IP), mycophenolate mofetil (20 mg/kg PO) plus 0.9% NaCl (6 mL/kg IP), methylcellulose (1.66 mL/kg PO) plus cyclosporine (5 mg/kg IP), and mycophenolate mofetil (20 mg/kg PO) plus cyclosporine (5 mg/kg IP). After 14 days a bile fistula was installed to measure the biliary excretion of the immunosuppressants and their metabolites. After 90 minutes blood was taken to determine their concentrations in blood or serum by HPLC. Cyclosporine significantly decreased the serum concentration of mycophenolic acid by 39% and increased, not significantly, that of 7-O-mycophenolic acid glucuronide by 53%. The biliary excretion of 7-O-mycophenolic acid glucuronide was significantly reduced by cyclosporine by 57%, whereas that of mycophenolic acid was not affected. Mycophenolate mofetil did not show a significant effect on either the blood concentration or the biliary excretion of cyclosporine and its metabolites AM1, AM9, AM1c, and AM4N. Cyclosporine significantly decreased the serum concentration of active mycophenolate acid and increased, not significantly, the serum concentration of inactive 7-O-mycophenolic acid glucuronide, presumably by reducing the biliary excretion of this inactive metabolite.
authors.affiliation: Institute of Pharmacology, Medical School Hannover, 30623 Hannover, Germany. michael_deters2002@yahoo.de
authors.forename: Michael
authors.initials: M
authors.lastname: Deters
authors.forename: Gabriele
authors.initials: G
authors.lastname: Kirchner
authors.forename: Therese
authors.initials: T
authors.lastname: Koal
authors.forename: Klaus
authors.initials: K
authors.lastname: Resch
authors.forename: Volkhard
authors.initials: V
authors.lastname: Kaever
mesh_terms: D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000737:chemistry / Q000378:metabolism; D001658:Biliary Fistula / Q000188:drug therapy / Q000503:physiopathology; D001663:Bilirubin / Q000097:blood / Q000737:chemistry; D001835:Body Weight / Q000187:drug effects; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D007274:Injections, Intraperitoneal; D008297:Male; D009173:Mycophenolic Acid / Q000378:metabolism* / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001647:Bile Acids and Salts; D016572:Cyclosporine; D009173:Mycophenolic Acid; D001663:Bilirubin