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. 2013 Mar;43(3):229-35.
doi: 10.3109/00498254.2012.713531. Epub 2012 Aug 30.

Mycophenolic acid glucuronide is transported by multidrug resistance-associated protein 2 and this transport is not inhibited by cyclosporine, tacrolimus or sirolimus

Chirag G Patel  1 , Ken Ogasawara, Fatemeh Akhlaghi
Affiliations

Mycophenolic acid glucuronide is transported by multidrug resistance-associated protein 2 and this transport is not inhibited by cyclosporine, tacrolimus or sirolimus

Chirag G Patel et al. Xenobiotica. 2013 Mar.

Abstract

1. The purpose of this study was to investigate the contribution of MRP2 to the efflux of mycophenolic acid (MPA), and its phenyl glucuronide (MPAG) and acyl glucuronide (AcMPAG) metabolites, using Madin-Darby canine kidney II cells stably transfected with human MRP2 gene (MDCKII/MRP2 cells). 2. Compared to parental MDCKII cells, MPAG was significantly translocated from basolateral (BL) to apical (AP) side in MDCKII/MRP2 cells, indicating MPAG is a substrate for MRP2. AcMPAG is highly translocated from BL to AP side in both cells, suggesting that AcMPAG is actively secreted possibly through an efflux transporter other than MRP2. Appreciable translocation of MPA was not observed in MDCKII/MRP2 cells. 3. Furthermore, using MRP2-expressing Sf9 membrane vesicles, the Michaelis-Menten constant (Km) value for MRP2-mediated MPAG transport was calculated at 224.2 ± 42.7 µM. In the vesicle system, cyclosporine, tacrolimus and sirolimus did not inhibit the uptake of MPAG via MRP2. 4. These findings indicate that only MPAG not MPA and AcMPAG is a substrate for MRP2 and that the interaction between MPAG and concomitantly administered immunosuppressive agents does not occur at MRP2 level.

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Conflict of interest statement

Declaration of Interest: The authors have no conflicts of interest to report. The authors alone are responsible for the content and writing of this manuscript.

Figures

Figure 1
Figure 1
(A) Transepithelial transport of mycophenolic acid (MPA), (B) Mycophenolic acid glucuronide (MPAG) and (C) Acyl mycophenolic acid glucuronide (AcMPAG) in a transwell monolayer of MDCKII/MRP2 and MDCKII/Par cells. Efflux ratios were calculated as BL to AP/AP to BL. Close symbols represent efflux ratio for each analyte in MDCKII/MRP2 cells and open symbols represent data obtained from MDCKII/Par cells. Two concentrations for each analyte, representing low and high clinical observed levels were studied. Each data point is the average of two observations.
Figure 2
Figure 2
Inhibitory effects of cyclosporine (CsA), tacrolimus (TAC) and sirolimus (SIR) on the transcellular transport of mycophenolic acid glucuronide (MPAG) across MDCKII/MRP2 cells. Efflux ratios were then calculated as BL to AP/AP to BL. MPAG concentration was 50 mg/L and the incubation time was 3 hours. Values represent mean ± SE for three replicates.
Figure 3
Figure 3
(A) Concentration dependence of ATP-dependent uptake of mycophenolic acid glucuronide (MPAG) by MRP2-expressing membrane vesicles. Vesicles were incubated at 37°C for 5 min with various concentration of MPAG. ATP-dependent transport activity was calculated by subtracting the transport activity in the presence of AMP from that in the presence of ATP. Values represent mean ± SE for three replicates. (B & C) Inhibitory effects of CsA, TAC and SIR on the ATP-dependent uptake of MPAG (B) and CDCF, a specific MRP2 substrate (C) by MRP2-expressing membrane vesicles. Vesicles were incubated at 37°C for 5 min with 30 μM MPAG (B) or 5 μM CDCF (C) in the presence of immunosuppressive agents cyclosporine (CsA), tacrolimus (TAC) and sirolimus (SIR). MK-571 was used as the inhibitor of MRP2. ATP-dependent transport activity was calculated by subtracting the transport activity in the presence of AMP from that in the presence of ATP. Values represent mean ± SE for three replicates.
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