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Westley IS, Morris RG, Evans AM, Sallustio BC.
Glucuronidation of mycophenolic acid by Wistar and
Mrp2 deficient TR- rat liver microsomes.
Drug Metab Dispos. 2007 Oct 1
The Queen Elizabeth Hospital.
In humans, mycophenolic acid (MPA) is metabolised
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 to
control Wistar rats, suggesting a difference in the capacity of
the TR- rats to metabolise MPA in situ. There is very little
information regarding the phase 2 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
nmol/min/mg and 0.65 nmol/min/mg respectively (p=0.33). Km
values for control and TR- microsomes were 0.47 mM and 0.50 mM
respectively (p=0.81). The mean (SEM) ratios of MPAGe formation
by Wistar rat liver microsomes incubated with 50 microM MPA +
inhibitor versus 50 microM MPA alone were: MPAGa 1.2(0.1); CsA
0.7(0.1)*; AM1 2.2(0.3)*; AM1c 1.2(0.2); and AM9 1.0(0.2)
(*p<0.05). Our results suggest that lower in situ
glucuronidation of MPA in TR- rats maybe due to inhibition of
glucuronidation by endogenous and exogenous compounds that
accumulate in the transporter deficient rat. Whilst, CsA
inhibits glucuronidation of MPA, its metabolite AM1 enhances
MPAGe formation by rat liver microsomes.
PMID: 17908922
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