JAIN ET AL PHARMACOKINETICS OF MYCOPHENOLIC ACID PHARMACOKINETICS AND PHARMACODYNAMICS Pharmacokinetics of Mycophenolic Acid after Mycophenolate Mofetil Administration in Liver Transplant Patients Treated with Tacrolimus Ashok Jain, MD, Raman Venkataramanan, PhD, FCP, Imad S. Hamad, MD, Sheila Zuckerman, MS, Shimin Zhang, BS, Jackie Lever, MS, Vijay S. Warty, PhD, and John J. Fung, MD, PhD M ycophenolate mofetil (MMF; morpholinoethyl ester of mycophenolic acid [MPA]) is the pro- drug of MPA. Mycophenolic acid is a potent, noncom- petitive inhibitor of inosine monophosphate dehydro- genase and prevents de novo synthesis of guanosine nucleotides and blocks T and B cell proliferation. 1-3 Af- ter oral administration, mycophenolate mofetil is rap- idly converted to MPA in the body and is excreted as the glucuronide conjugate (MPAG) in the urine and bile. Three separate double-blind randomized trials in- volving MMF have been carried out in primary kidney transplant patients in Europe, United States, Canada, and Australia. In these studies, the efficacy of MMF in combination with cyclosporine and steroid was com- pared with the efficacy of cyclosporine, steroid, and azathioprine or that of cyclosporine, steroid, and pla- cebo. Significantly reduced rejection episodes were noted with MMF therapy in all three trials. 4-6 Several clinical trials have documented tacrolimus to be an effective immunosuppressive drug following liver transplantation (LTx). 7-11 The safety and efficacy of MMF in combination with tacrolimus have recently been studied in renal transplant patients. In the present study, we (1) evaluated the pharmacokinetics of MPA in primary LTx patients within the first 30 days after transplantation and initiation of MMF therapy and (2) examined the trough concentrations of MPA during the first few weeks after transplantation in separate groups of primary liver transplant patients treated with tacro- limus and MMF. 268 J Clin Pharmacol 2001;41:268-276 From the School of Pharmacy (Dr. Venkataramanan), Thomas E. Starzl Transplantation Institute (Dr. Jain, Dr. Hamad, Dr. Warty, Dr. Fung, Ms. Zuckerman, Ms. Zhang), and School of Nursing (Ms. Lever), University of Pittsburgh, Pittsburgh, Pennsylvania. Submitted for publication September 9, 1998; revised version accepted September 5, 2000. Address for reprints: Raman Venkataramanan, PhD, 718 Salk Hall, University of Pittsburgh, Pittsburgh, PA 15261. The pharmacokinetics of mycophenolic acid (MPA) was studied after oral administration of mycophenolate mofetil (MMF) in 8 liver transplant patients. The mean (± SD) maxi- mum 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 se- rum 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 dys- function. In 7 primary liver transplant patients on the same dose of MMF, the trough plasma concentrations of MPA dur- ing the first week of therapy ranged from < 0.3 to 1.5 μg/ml. The MPA concentrations increased by several folds during the next few weeks, which correlates well with increases in se- rum albumin concentrations. Changes in albumin appear to partially contribute to the variations in the pharmacokinetics of MPA in liver transplant patients. Journal of Clinical Pharmacology, 2001;41:268-276 ©2001 the American College of Clinical Pharmacology