mycophenolic-acid-glucuronide and Liver-Diseases

The exposure of mycophenolic acid in live donor liver transplant patients (those receiving a partial hepatic volume) in comparison to deceased donor liver transplant patients (those receiving the whole hepatic volume) after administration of mycophenolate mofetil has not been reported earlier. The aim of the present study is to compare the pharmacokinetics parameters of mycophenolic acid and mycophenolic acid glucuronide in live donor liver transplant patients versus deceased donor liver transplant patients. Twelve live donor liver transplant and 12 deceased donor liver transplant recipients were studied over a dosing interval after intravenous administration of mycophenolate mofetil. The maximum concentration (Cmax) and the area under the plasma concentration versus time curve (AUC) for mycophenolic acid in live donor liver transplant patients were significantly higher than in deceased donor liver transplant patients (Cmax/AUC: live donor liver transplant patients: 16.1 +/- 6.6 microg/mL/43.9 +/- 12.6 microg/mL.h vs deceased donor liver transplant patients: 10.7 +/- 2.0 microg/mL/28.9 +/- 7.1 microg/mL.h; P = .046/.002). The volume of distribution was higher in the deceased donor liver transplant patients compared with live donor liver transplant patients. However, the mean plasma concentration at 12 hours (Clast), drug disposition rate constant, half-life (t 1/2), and mean residence time were similar in both groups. The mean plasma concentration of mycophenolic acid glucuronide was 1.4 to 2.0 times higher in deceased donor liver transplant patients compared with live donor liver transplant patients. These observations point to the need to use a lower dosage (approximately 30%) of mycophenolate mofetil in live donor liver transplant patients compared with deceased donor liver transplant patients.

Topics: Area Under Curve; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Glucuronides; Humans; Immunosuppressive Agents; Injections, Intravenous; Liver Diseases; Liver Transplantation; Living Donors; Male; Metabolic Clearance Rate; Middle Aged; Mycophenolic Acid; Postoperative Period; Prospective Studies; Tissue Donors

The pharmacokinetics of mycophenolic acid (MPA) was studied after oral administration of mycophenolate mofetil (MMF) in 8 liver transplant patients. The mean (+/- SD) maximum MPA plasma concentration of 10.6 (+/- 7.5) mg/ml was achieved within 0.5 to 5 hours. The mean (+/- SD) steady-state area under the plasma concentration versus time curve (AUC(0-12)) was 40 (+/- 30.9) mg/ml/h. The mean (+/- SD) half-life was 5.8 (+/- 3.8) hours. There was poor correlation between trough blood concentrations of tacrolimus (r = -0.004) or serum creatinine (r = 0.689) with MPA AUC, while the serum bilirubin concentrations correlated (r = 0.743) well with MPA AUC, suggesting impairment in MPA conjugation in patients with liver dysfunction. The mean (+/- SD) ratio of the AUC of mycophenolic acid glucuronide (MPAG) to MPA was 64 (+/- 84), which correlated significantly with serum creatinine (r = 0.72) but not with serum bilirubin concentrations (r = 0.309), indicating accumulation of MPAG in patients with renal dysfunction. In 7 primary liver transplant patients on the same dose of MMF, the trough plasma concentrations of MPA during the first week of therapy ranged from < 0.3 to 1.5 microg/ml. The MPA concentrations increased by several folds during the next few weeks, which correlates well with increases in serum albumin concentrations. Changes in albumin appear to partially contribute to the variations in the pharmacokinetics of MPA in liver transplant patients.

Topics: Adult; Aged; Area Under Curve; Bile; Bilirubin; Chromatography, High Pressure Liquid; Creatinine; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glucuronates; Glucuronides; Half-Life; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prodrugs; Serum Albumin; Tacrolimus; Time Factors