Abstract
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). Km 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 μM MPA plus inhibitor versus 50 μM 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.
Footnotes
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This work was funded, in part, by a grant-in-aid from the Australian Kidney Foundation.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.017210.
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ABBREVIATIONS: MPA, mycophenolic acid; MPAGe, mycophenolate ether glucuronide; MPAGa, mycophenolate acyl glucuronide; UGT, UDP glucuronosyltransferase(s); CsA, cyclosporine; CL, clearance; UDPGA, UDP-glucuronic acid; BSA, bovine serum albumin; HLM, human liver microsome(s); HPLC, high-performance liquid chromatography; CLint, intrinsic clearance.
- Received June 21, 2007.
- Accepted September 27, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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