Intraindividual and Interindividual Variations in the Pharmacokinetics of Mycophenolic Acid in Liver Transplant Patients

Abstract

The authors evaluated the intraindividual and interindividual variations in the pharmacokinetics of mycophenolic acid after oral administration of mycophenolate mofetil in 10 liver transplant patients. Mycophenolic acid and its metabolite, mycophenolic acid glucuronide, were measured in plasma and urine by high-pressure liquid chromatography. The plasma protein binding of mycophenolic acid was determined by ultrafiltration. The maximum concentration of mycophenolic acid in plasma increased significantly (P < or = .05) with time from 9.1 +/- 7.2 microg/mL (<1 week) to 36.7 +/- 15.6 microg/mL (1 month). The area under the plasma concentration versus time curve of mycophenolic acid also increased significantly with time, from 50.8 +/- 42.1 microg x h/mL to 118.0 +/- 57.6 microg x h/mL (P < or = .05). The plasma protein binding of mycophenolic acid increased from 92% to 98%, and the apparent oral clearance [CL/F] decreased from 32.9 +/- 21.4 L/h during the first study period to 9.0 +/- 4.4 L/h (P < or = .05) during the third study period. The apparent intrinsic clearance of mycophenolic acid did not change significantly over time. The ratio of the area under the curve of mycophenolic acid glucluronide to mycophenolic acid in plasma decreased with time (25.5 +/- 21.2 vs 8.0 +/- 3.3) but did not reach statistical significance. The increased binding of mycophenolic acid to plasma proteins with time after transplantation appeared to contribute to the intraindividual variation, whereas differences in the ability of the liver to metabolize mycophenolic acid between patients appear to contribute to the large interindividual variation in the pharmacokinetics of mycophenolic acid. The observations in this study support the concept of measuring the unbound concentration of mycophenolic acid to optimize immunosuppressive drug therapy with mycophenolic acid.