Factors contributing to the variability in the disposition of mycophenolic acid

Mycophenolic acid (MPA), the active moiety of the immunosuppressive drug mycophenolate mofetil (MMF), is highly bound to plasma protein albumin and is primarily eliminated by glucuronidation (MPAG). Plasma protein binding and drug metabolizing capacity are highly variable in liver transplant (LTx) patients. So, we hypothesized that there will be large intra- and inter-individual variations in the pharmacokinetics of MPA in LTx patients and studied the pharmacokinetics of MPA at three time points after transplantation. The observed large intra-individual variations in the pharmacokinetics of MPA were primarily due to time dependent changes in plasma protein binding of MPA while the observed large inter-individual differences were due to variations in plasma protein binding (PPB) and the intrinsic clearance (CL_int) of MPA.; Using an isolated rat liver perfusion system, we have shown that a reduction in albumin concentration increased the unbound fraction (Fu) and the total clearance (CL) of MPA and that endotoxemia decreased the conjugation of MPA and biliary clearance of MPAG. In Gunn rats that are deficient in UGT1A, marked reduction in intrinsic clearance of MPA was observed in both in vitro and in vivo studies in comparison to Sprague-Dawley (SD) rats. The kidneys (in SD rats) appear to contribute less than 10% to the overall metabolism of MPA. Acute renal failure increased the unbound fraction and decreased the intrinsic clearance of MPA. Co-administration of tacrolimus impaired urinary and biliary clearance of MPAG.; Changes in protein binding and intrinsic clearance contributed to the variability in the pharmacokinetics of MPA. Large variability in the pharmacokinetics of MPA warrants the need for therapeutic drug monitoring (TDM) of MPA in liver transplant patients. Since MPA is a low clearance drug and the unbound concentration of MPA is responsible for the pharmacological response, it is important to measure unbound concentration of MPA in order to optimize therapy in transplant patients.