Westley Ian S, Morris Raymond G, Evans Allan M, Sallustio Benedetta C
Department of Clinical Pharmacology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA, Australia 5011.
Drug Metab Dispos. 2008 Jan;36(1):46-50. doi: 10.1124/dmd.107.017210. Epub 2007 Oct 1.
In humans, mycophenolic acid (MPA) is metabolized primarily by glucuronidation in the liver to mycophenolate ether glucuronide (MPAGe) and mycophenolate acyl glucuronide (MPAGa). We have previously reported that in perfused livers of TR(-) rats (lacking the Mrp2 transporter), the clearance and hepatic extraction ratio of MPA were significantly lower compared with control Wistar rats, suggesting a difference in the capacity of the TR(-) rats to metabolize MPA in situ. There is very little information regarding the phase II metabolic capabilities of TR(-) rats; therefore, the aim of this study was to investigate the in vitro glucuronidation of MPA in Wistar and TR(-) rat liver microsomal protein. A second aim was to determine whether MPAGa, cyclosporine (CsA), and/or its metabolites AM1, AM1c, and AM9 inhibit the metabolism of MPA to MPAGe in rat liver microsomes. MPAGe formation rates by Wistar and TR(-) microsomes were 0.48 and 0.65 nmol/min/mg, respectively (p = 0.33). K(m) values for control and TR(-) microsomes were 0.47 and 0.50 mM, respectively (p = 0.81). The mean (S.E.M.) ratios of MPAGe formation by Wistar rat liver microsomes incubated with 50 microM MPA plus inhibitor versus 50 microM MPA alone were MPAGa 1.2 (0.1), CsA 0.7 (0.1) (p < 0.05), AM1 2.2 (0.3) (p < 0.05), AM1c 1.2 (0.2), and AM9 1.0 (0.2). Our results suggest that lower in situ glucuronidation of MPA in TR(-) rats may be because of inhibition of glucuronidation by endogenous and exogenous compounds that accumulate in the transporter-deficient rat. Whereas CsA inhibits glucuronidation of MPA, its metabolite AM1 enhances MPAGe formation by rat liver microsomes.
在人体内，霉酚酸（MPA）主要在肝脏中通过葡糖醛酸化代谢为霉酚酸醚葡糖醛酸酯（MPAGe）和霉酚酸酰基葡糖醛酸酯（MPAGa）。我们之前报道过，在TR(-)大鼠（缺乏Mrp2转运蛋白）的灌注肝脏中，MPA的清除率和肝脏提取率与对照Wistar大鼠相比显著降低，这表明TR(-)大鼠原位代谢MPA的能力存在差异。关于TR(-)大鼠II相代谢能力的信息非常少；因此，本研究的目的是研究Wistar和TR(-)大鼠肝微粒体蛋白中MPA的体外葡糖醛酸化。第二个目的是确定MPAGa、环孢素（CsA）和/或其代谢产物AM1、AM1c和AM9是否抑制大鼠肝微粒体中MPA向MPAGe的代谢。Wistar和TR(-)微粒体形成MPAGe的速率分别为0.48和0.65 nmol/分钟/毫克（p = 0.33）。对照和TR(-)微粒体的K(m)值分别为0.47和0.50 mM（p = 0.81）。用50 microM MPA加抑制剂孵育的Wistar大鼠肝微粒体与单独用50 microM MPA孵育相比，MPAGe形成的平均（标准误）比率分别为：MPAGa 1.2（0.1），CsA 0.7（0.1）（p < 0.05），AM1 2.2（0.3）（p < 0.05），AM1c 1.2（0.2），AM9
