Gaganis Paraskevi, Miners John O, Knights Kathleen M
Department of Clinical Pharmacology, Flinders University and Flinders Medical Centre, Bedford Park, Adelaide, Australia.
Biochem Pharmacol. 2007 May 15;73(10):1683-91. doi: 10.1016/j.bcp.2007.01.030. Epub 2007 Jan 28.
Mefenamic acid, a non-steroidal anti-inflammatory drug (NSAID), is used commonly to treat menorrhagia. This study investigated the glucuronidation kinetics of flufenamic, mefenamic and niflumic acid using human kidney cortical microsomes (HKCM) and recombinant UGT1A9 and UGT2B7. Using HKCM Michaelis-Menten (MM) kinetics were observed for mefenamic (K(m)(app) 23 microM) and niflumic acid (K(m)(app) 123 microM) glucuronidation, while flufenamic acid exhibited non-hyperbolic (atypical) glucuronidation kinetics. Notably, the intrinsic renal clearance of mefenamic acid (CL(int) 17+/-5.5 microL/minmg protein) was fifteen fold higher than that of niflumic acid (CL(int) 1.1+/-0.8 microL/minmg protein). These data suggest that renal glucuronidation of mefenamic acid may result in high intrarenal exposure to mefenamic acyl-glucuronide and subsequent binding to renal proteins. Diverse kinetics were observed for fenamate glucuronidation by UGT2B7 and UGT1A9. Using UGT2B7 MM kinetics were observed for flufenamic (K(m)(app) 48 microM) and niflumic acid (K(m)(app) 135 microM) glucuronidation and atypical kinetics with mefenamic acid. Similarity in K(m)(app) between HKCM and UGT2B7 suggests that UGT2B7 may be the predominant renal UGT isoform catalysing niflumic acid glucuronidation. In contrast, UGT1A9 glucuronidation kinetics were characterised by negative cooperativity with mefenamic (S(50) 449 microM, h 0.4) and niflumic acid (S(50) 7344 microM, h 0.4) while atypical kinetics were observed with flufenamic acid. Additionally, potent inhibition of the renal glucuronidation of the UGT substrate 'probe' 4-methylumbelliferone by flufenamic, mefenamic and niflumic acid was observed. These data suggest that inhibitory metabolic interactions may occur between fenamates and other substrates metabolised by UGT2B7 and UGT1A9 in human kidney.
甲芬那酸是一种非甾体抗炎药（NSAID），常用于治疗月经过多。本研究使用人肾皮质微粒体（HKCM）以及重组UGT1A9和UGT2B7研究了氟芬那酸、甲芬那酸和尼氟酸的葡萄糖醛酸化动力学。使用HKCM时，观察到甲芬那酸（表观米氏常数K(m)(app) 23 microM）和尼氟酸（表观米氏常数K(m)(app) 123 microM）葡萄糖醛酸化的米氏动力学，而氟芬那酸表现出非双曲线（非典型）葡萄糖醛酸化动力学。值得注意的是，甲芬那酸的内在肾清除率（CL(int) 17±5.5微升/分钟毫克蛋白）比尼氟酸（CL(int) 1.1±0.8微升/分钟毫克蛋白）高15倍。这些数据表明，甲芬那酸的肾葡萄糖醛酸化可能导致肾内甲芬那酸酰基葡萄糖醛酸的高暴露以及随后与肾蛋白的结合。观察到UGT2B7和UGT1A9对芬那酸盐葡萄糖醛酸化的动力学不同。使用UGT2B7时，观察到氟芬那酸（表观米氏常数K(m)(app) 48 microM）和尼氟酸（表观米氏常数K(m)(app) 135 microM）葡萄糖醛酸化的米氏动力学以及甲芬那酸的非典型动力学。HKCM和UGT2B7之间表观米氏常数的相似性表明，UGT2B7可能是催化尼氟酸葡萄糖醛酸化的主要肾UGT同工酶。相比之下，UGT1A9葡萄糖醛酸化动力学的特征是与甲芬那酸（半最大底物浓度S(50) 449 microM，Hill系数h 0.4）和尼氟酸（半最大底物浓度S(50) 7344 microM，Hill系数h 0.4）呈负协同作用，而氟芬那酸表现出非典型动力学。此外，观察到氟芬那酸、甲芬那酸和尼氟酸对UGT底物“探针”4-甲基伞形酮的肾葡萄糖醛酸化有强效抑制作用。这些数据表明，在人肾中，芬那酸盐与其他由UGT2B7和UGT1A9代谢的底物之间可能发生抑制性代谢相互作用。
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