Investigation on the mechanism of transmembrane transport of mycophenolate mofetil and its active metabolite mycophenolic acid / 中国药学杂志

ABSTRACT

OBJECTIVE: To investigate the mechanism of transmembrane transport of mycophenolate mofetil (MMF) and its active metabolite mycophenolic acid (MPA). METHODS: Caco-2 cell monolayer model was developed for MMF and MPA transport experiment, and the LC-MS/MS method was used for the determination of MMF and MPA concentration in transport medium. The apparent permeability coefficient (Papp) and efflux ratio (Pratio) were calculated and used for the evaluation of the ability of drug transport and drug efflux across Caco-2 cell monolayer. RESULTS: The Papp of MPA in two-way transport experiment (Papp,ab and Papp,ba) at 10, 50 and 100 μmol · L-1 were(9.70 ± 0.40) × 106 cm · s-1 [(13.52 ± 0.28) × 106 cm · s-1], (9.35 ± 0.62) × 106 cm · s-1 [(11.38 ± 0.59) × 106 cm · s-1], (8.69 ± 0.69) × 106 cm · s-1 [(10.53 ± 0.64) × 106 cm · s-1], respectively. Pratio were 1.39, 1.22 and 1.22, respectively. Pratio of MPA was reduced by verapamil, a well-known P-glycoprotein inhibitor. MMF was mostly hydrolyzed to MPA during the transport process across the Caco-2 cell monolayer. The amount of MPA transported increased with time, but the amount of MMF transported changed not significantly over time and no significant effect of verapamil was observed. CONCLUSION: The transmembrane transport of MPA is affected by active transport efflux mediated by transporter with P-gp involved. No effect of P-gp is found in MMF transmembrane transport, which is passive transport.