The pharmacokinetics and pharmacodynamics of mycophenolic acid in kidney transplant recipients

Mycophenolic acid (MPA) is a common immunosuppressive agent administered as combined therapy with either cyclosporine (CsA) or tacrolimus (TAC). Since transplant patients are maintained on numerous other medications for co-existing conditions, drug interactions are commonly encountered in transplantation. A pharmacokinetic drug interaction study for MPA with either CsA or TAC was performed in 24 stable kidney transplant recipients. Patients with concomitant CsA displayed higher exposure to MPA as compared to patients on TAC. This was in contrast to results reported by similar studies. We owed it to the fact that our group of patients on CsA was also maintained on concomitant ketoconazole due to its CsA sparing effect. Both CsA and ketoconazole are inhibitors of metabolic enzymes as well as active efflux transporters located in the intestine, kidney and liver. To evaluate our hypothesis, a pharmacokinetic study for MPA with or without ketoconazole was performed in adult male Sprague Dawley rats. We did not observe any differences in pharmacokinetics of MPA between the two groups. Thereafter drug interactions studies (at low and high physiologic relevant concentration) were conducted in Madine Darby Canine Kidney cells transfected with human multi-drug resistance protein-2 gene (MRP2) for commonly co-administered medication including CsA, TAC, sirolimus, rifampicin and ketoconazole. All the agents except the low concentration of TAC were found to inhibit the active biliary efflux of the phenyl glucuronide metabolite of MPA that it secreted by biliary route.; A second clinical study was conducted to investigate the effect of diabetes on the pharmacokinetics of MPA as well as its effect on immune response. The activity of inosine 5' monophosphate dehydrogenase (IMPDH), the molecular target for MPA was used as the biomarker for immune response. The study was performed in 18 stable kidney transplant recipients, half of which were diabetic. We did not observe any differences in the pharmacokinetic of MPA between the two groups; however the diabetic transplant patients displayed significantly lower immune response. The activity of IMPDH was not found to be different between controlled and uncontrolled diabetics transplant patients, indicating that diabetes may alter immune response and surprisingly it is independent of glycemic control.