Glucuronidation of mycophenolic acid by Wistar and Mrp2-deficient TR- rat liver microsomes.
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.
Westley
Ian S
IS
Department of Clinical Pharmacology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA, Australia 5011.
Morris
Raymond G
RG
Evans
Allan M
AM
Sallustio
Benedetta C
BC
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology; D005966:Glucuronidase / Q000378:metabolism; D020719:Glucuronides / Q000378:metabolism / Q000493:pharmacokinetics; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006868:Hydrolysis; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D020719:Glucuronides; C113145:mycophenolic acid glucuronide; D016572:Cyclosporine; D014453:Glucuronosyltransferase; D005966:Glucuronidase; D009173:Mycophenolic Acid