In vitro mechanistic study on mycophenolate mofetil drug interactions: effect of prednisone, cyclosporine, and others

Area of Science:

• Pharmacology
• Drug Metabolism and Pharmacokinetics
• Drug Interactions

Background:

• High inter-individual variability in mycophenolate mofetil (MMF) exposure is often linked to drug-drug interactions (DDIs).
• Understanding these DDIs is crucial for optimizing MMF therapy, particularly in patients receiving multiple medications.

Purpose of the Study:

• To systematically investigate the in vitro influence of co-administered medications on mycophenolic acid (MPA) pharmacokinetics (PK).
• To provide mechanistic insights into metabolic interactions involving steroids, cyclosporine (CsA), and MMF.
• To assess DDI risks of commonly co-administered drugs with MMF.

Main Methods:

• Human hepatocyte induction studies to assess metabolic enzyme activity.
• Transporter substrate/inhibition studies using human embryonic kidney 293 cells.
• Vesicle membrane studies to evaluate multidrug resistance-associated protein 2 (MRP2) interactions.
• Evaluation of seven commonly co-administered medications with MMF.

Main Results:

• Prednisolone (active metabolite of prednisone) induces UGT1A9 and UGT2B7, increasing MPA metabolism to MPAG.
• Cyclosporine A (CsA) inhibits OATP1B1 and OATP1B3, affecting MPAG transport.
• Salvia miltiorrhiza inhibits OATP and OAT3, impacting MPAG hepatic uptake and renal excretion.
• No significant inhibition of MRP2-mediated MPAG efflux by prednisolone or CsA was observed.

Conclusions:

• Identified DDIs involving prednisolone, CsA, and Salvia miltiorrhiza contribute to MMF exposure variability.
• These findings support the development of mechanistic MMF PK models.
• Mechanistic understanding facilitates personalized MMF dosing strategies.