The pharmacokinetics of mycophenolic acid in rats with orotic acid induced nonalcoholic fatty liver disease

Abstract

Post-transplantation nonalcoholic fatty liver disease (NAFLD) is common in liver transplant recipients. Changes in the expression levels and activities of drug-metabolizing enzymes and drug transporters have been reported in patients with NAFLD and relevant rodent models. Here, we evaluated whether the pharmacokinetics of mycophenolic acid (MPA), an immunosuppressant, would be altered in rats with NAFLD. NAFLD was induced by feeding a diet containing 1% (w/w) orotic acid for 20 days. The extent of hepatic glucuronidation of MPA to a major metabolite, mycophenolic acid-7-O-glucuronide (MPAG), did not differ between rats with NAFLD and controls. The expression levels of hepatic multidrug resistance-associated protein 2, responsible for biliary excretion of MPAG, were comparable in rats with NAFLD and controls; the biliary excretion of MPAG was also similar in the two groups. Compared with control rats, rats with NAFLD did not exhibit significant changes in the areas under the plasma concentration – time curves of MPA or MPAG after intravenous (5 mg/kg) or oral (10 mg/kg) administration of MPA. However, delayed oral absorption of MPA was observed in rats with NAFLD compared with controls; the MPA and MPAG peak plasma concentrations fell significantly and the times to achieve them were prolonged following oral administration of MPA.

Changes in digoxin pharmacokinetics associated with hepatic P‐glycoprotein upregulation in rats with non‐alcoholic fatty liver disease

“…Jugular vein cannulation (for drug administration), carotid artery cannulation (for blood sampling), and bile duct cannulation (for bile juice sampling) were performed as described previously [23,27]. The rats were not restrained.…”

“…Blood samples (approximately 200 μl) were collected via the carotid artery from control (n = 7) and NAFLD (n = 8) rats at 0 (blank), 1 (end of infusion), 5, 10, 15, 30, 45, 60, 90, 120, 180, and 240 min after intravenous infusion commenced; samples were immediately centrifuged. The preparation and handling of 24-h urine samples (Ae 0-24 h ) and gastrointestinal (GI) tract (contents and feces) samples at 24 h (GI 24 h ) have been described previously [23,27]. One hundred-microliter aliquots of plasma, urine, and gastrointestinal tract samples were stored at −20°C prior to LC-MS/MS analysis of digoxin.…”