■霉酚酸酯(MMF)和共同给药之间基于代谢和转运蛋白的药物-药物相互作用(DDI)可能是MMF暴露中高度个体差异的关键因素。本研究系统地评估了联合用药对霉酚酸(MPA)药代动力学(PK)过程的影响,特别是提供类固醇之间代谢相互作用的机械证据,环孢菌素(CsA),和MMF。
■基于先前的研究,我们假设有三种主要的DDI途径在体内影响MMFPK。人类肝细胞诱导研究,使用人胚肾293细胞进行转运体底物/抑制研究,和使用囊泡膜的多药耐药相关蛋白2(MRP2)底物/抑制研究进行了评估三联疗法中代谢相互作用的机制证据。进一步评估了与临床实践中通常与MMF共同施用的七种药物相关的潜在DDI风险。
■体外结果表明泼尼松龙,泼尼松的活性代谢产物,诱导尿苷5'-二磷酸葡萄糖醛酸基转移酶(UGT)的酶活性,特别是UGT1A9和UGT2B7同工型,导致MPA向MPA葡糖苷酸(MPAG)的代谢增加。在CsA处理的人肝细胞中未观察到这种诱导潜力。CsA抑制有机阴离子转运多肽(OATP)1B1-和OATP1B3-介导的MPAG。泼尼松龙和CsA对MRP2介导的MPAG外排无抑制作用。丹参显著抑制有机阴离子转运多肽和OAT3活性,提示它影响MPAG的肝摄取和肾排泄,导致体内MPAG暴露增加。
■这些确定的因素可能导致MMF暴露的高度个体间差异,并促进机械MMFPK模型和个性化治疗的进一步发展。
UNASSIGNED: The metabolism- and transporter-based drug-drug interactions (DDIs) between mycophenolate mofetil (MMF) and co-administered medications may be key factors for the high individual variability in MMF exposure. This study systematically assessed the influence of co-medications on the mycophenolic acid (MPA) pharmacokinetic (PK) process in vitro, particularly to provide mechanistic evidence of the metabolic interaction among steroids, cyclosporine (CsA), and MMF.
UNASSIGNED: Based on a previous study, we hypothesized that there are three main DDI pathways affecting MMF PK in vivo. A human hepatocyte induction study, transporter substrate/inhibition study using human embryonic kidney 293 cells, and multidrug resistance-associated protein 2 (MRP2) substrate/inhibition study using vesicle membrane were conducted to assess the mechanistic evidence of the metabolic interaction in triple therapies. The potential DDI risks associated with seven medications commonly co-administered with MMF in clinical practice were further evaluated.
UNASSIGNED: The in vitro results suggested that
prednisolone, the active metabolite of prednisone, induces the enzymatic activity of uridine 5\'-diphospho-glucuronosyltransferase (UGT), particularly the UGT1A9 and UGT2B7 isoforms, resulting in increased metabolism of MPA to MPA glucuronide (MPAG). This induction potential was not observed in CsA-treated human hepatocytes. CsA inhibits organic anion-transporting polypeptide (OATP) 1B1- and OATP1B3-mediated MPAG.
Prednisolone and CsA showed no inhibitory effect on MRP2-mediated MPAG efflux. Salvia miltiorrhiza significantly inhibited organic anion-transporting polypeptide and OAT 3 activities, suggesting that it affects the hepatic uptake and renal excretion of MPAG, causing increased MPAG exposure in vivo.
UNASSIGNED: These identified factors may contribute to the high inter-individual variability in MMF exposure and facilitate further development of mechanistic MMF PK models and individualized therapies.