The pharmacokinetic interaction between mycophenolic acid and cyclosporine revisited: A commentary on 'mycophenolic acid glucuronide is transported by multidrug resistance-associated protein 2 and this transport is not inhibited by cyclosporine, tacrolimus or sirolimus'

摘要

In the past 10 years, mycophenolic acid (MPA) has become a cornerstone agent in immunosuppressive therapy. Since the earliest pharmacokinetic studies, the crucial role of its glucuronidation has been highlighted (Bullingham et al., 1998). MPA is extensively metabolized to its inactive hydroxy-Beta-glucuronide (MPA-phenyl-glucuronide; MPAG) and the metabolite contributes to MPA enterohepatic circulation after deglucuronidation in the gut. This feature is important since it accounts for 10--61% of total MPA exposure (Bullingham et al., 1998). It is usually reflected as a second increase in the MPA time concentration curve, occurring 6-12 h after oral dosing. Clinically relevant differences in drug exposure depending on the calcineurin inhibitor (cyclosporine A or tacrolimus) given with mycophenolate mofetil (MMF) were described and attributed to an interaction with MPA enterohepatic cycling. The combination of MMF with tacrolimus as compared to cyclosporine in renal transplant recipients was found to give rise to higher residual concentrations and area under the concentration curves (AUC) of MPA (Hubner et al., 1999; Zucker et al., 1997).