Renal glucuronidation and multidrug resistance protein 2-/ multidrug resistance protein 4-mediated efflux of mycophenolic acid: Interaction with cyclosporine and tacrolimus

Azza A K El-Sheikh, Jan B. Koenderink, Alfons C. Wouterse, Petra H H Van Den Broek, Vivienne G M Verweij, Rosalinde Masereeuw, Frans G M Russel

Research output: Contribution to journalArticle

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Abstract

Mycophenolic acid (MPA) is an immunosuppressant used in transplant rejection, often in combination with cyclosporine (CsA) and tacrolimus (Tac). The drug is cleared predominantly via the kidneys, and 95% of the administered dose appears in urine as 7-hydroxy mycophenolic acid glucuronide (MPAG). The current study was designed to unravel the renal excretory pathway of MPA and MPAG, and their potential drug-drug interactions. The role of multidrug resistance protein (MRP) 2 and MRP4 in MPA disposition was studied using human embryonic kidney 293 (HEK293) cells overexpressing the human transporters, and in isolated, perfused kidneys of Mrp2-deficient rats and Mrp4-deficient mice. Using these models, we identified MPA as substrate of MRP2 and MRP4, whereas its MPAG appeared to be a substrate of MRP2 only. CsA inhibited MPAG transport via MRP2 for 50% at 8 μM (P < 0.05), whereas Tac had no effect. This was confirmed by cell survival assays, showing a 10-fold increase in MPA cytotoxicity (50% reduction in cell survival changed from 12.2 ± 0.3 μM to 1.33 ± 0.01 μM by MPA + CsA; P < 0.001) and in perfused kidneys, showing a 50% reduction in MPAG excretion (P < 0.05). The latter effect was observed in Mrp2-deficient animals as well, supporting the importance of Mrp2 in MPAG excretion. CsA, but not Tac, inhibited MPA glucuronidation by rat kidney homogenate and human uridine 5'-diphospho-glucuronosyltransferase- glucuronosyltransferase 1A9 (P < 0.05 and P < 0.01, respectively). We conclude that MPA is a substrate of both MRP2 and MRP4, but MRP2 is the main transporter involved in renal MPAG excretion. In conclusion, CsA, but not Tac, influences MPA clearance by inhibiting renal MPA glucuronidation and MRP2-mediated MPAG secretion.

Original languageEnglish
Pages (from-to)46-56
Number of pages11
JournalTranslational Research
Volume164
Issue number1
DOIs
Publication statusPublished - 1 Jan 2014

Fingerprint

Mycophenolic Acid
P-Glycoproteins
Tacrolimus
Cyclosporine
Kidney
Glucuronosyltransferase
Rats
Cell Survival
Substrates
Cells
P-glycoprotein 2
Drug interactions
Transplants
Hydroxy Acids
mycophenolic acid glucuronide
Uridine
Graft Rejection
Immunosuppressive Agents
Cytotoxicity
Drug Interactions

Cite this

El-Sheikh, Azza A K ; Koenderink, Jan B. ; Wouterse, Alfons C. ; Van Den Broek, Petra H H ; Verweij, Vivienne G M ; Masereeuw, Rosalinde ; Russel, Frans G M. / Renal glucuronidation and multidrug resistance protein 2-/ multidrug resistance protein 4-mediated efflux of mycophenolic acid : Interaction with cyclosporine and tacrolimus. In: Translational Research. 2014 ; Vol. 164, No. 1. pp. 46-56.
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abstract = "Mycophenolic acid (MPA) is an immunosuppressant used in transplant rejection, often in combination with cyclosporine (CsA) and tacrolimus (Tac). The drug is cleared predominantly via the kidneys, and 95{\%} of the administered dose appears in urine as 7-hydroxy mycophenolic acid glucuronide (MPAG). The current study was designed to unravel the renal excretory pathway of MPA and MPAG, and their potential drug-drug interactions. The role of multidrug resistance protein (MRP) 2 and MRP4 in MPA disposition was studied using human embryonic kidney 293 (HEK293) cells overexpressing the human transporters, and in isolated, perfused kidneys of Mrp2-deficient rats and Mrp4-deficient mice. Using these models, we identified MPA as substrate of MRP2 and MRP4, whereas its MPAG appeared to be a substrate of MRP2 only. CsA inhibited MPAG transport via MRP2 for 50{\%} at 8 μM (P < 0.05), whereas Tac had no effect. This was confirmed by cell survival assays, showing a 10-fold increase in MPA cytotoxicity (50{\%} reduction in cell survival changed from 12.2 ± 0.3 μM to 1.33 ± 0.01 μM by MPA + CsA; P < 0.001) and in perfused kidneys, showing a 50{\%} reduction in MPAG excretion (P < 0.05). The latter effect was observed in Mrp2-deficient animals as well, supporting the importance of Mrp2 in MPAG excretion. CsA, but not Tac, inhibited MPA glucuronidation by rat kidney homogenate and human uridine 5'-diphospho-glucuronosyltransferase- glucuronosyltransferase 1A9 (P < 0.05 and P < 0.01, respectively). We conclude that MPA is a substrate of both MRP2 and MRP4, but MRP2 is the main transporter involved in renal MPAG excretion. In conclusion, CsA, but not Tac, influences MPA clearance by inhibiting renal MPA glucuronidation and MRP2-mediated MPAG secretion.",
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Renal glucuronidation and multidrug resistance protein 2-/ multidrug resistance protein 4-mediated efflux of mycophenolic acid : Interaction with cyclosporine and tacrolimus. / El-Sheikh, Azza A K; Koenderink, Jan B.; Wouterse, Alfons C.; Van Den Broek, Petra H H; Verweij, Vivienne G M; Masereeuw, Rosalinde; Russel, Frans G M.

In: Translational Research, Vol. 164, No. 1, 01.01.2014, p. 46-56.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Renal glucuronidation and multidrug resistance protein 2-/ multidrug resistance protein 4-mediated efflux of mycophenolic acid

T2 - Interaction with cyclosporine and tacrolimus

AU - El-Sheikh, Azza A K

AU - Koenderink, Jan B.

AU - Wouterse, Alfons C.

AU - Van Den Broek, Petra H H

AU - Verweij, Vivienne G M

AU - Masereeuw, Rosalinde

AU - Russel, Frans G M

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Mycophenolic acid (MPA) is an immunosuppressant used in transplant rejection, often in combination with cyclosporine (CsA) and tacrolimus (Tac). The drug is cleared predominantly via the kidneys, and 95% of the administered dose appears in urine as 7-hydroxy mycophenolic acid glucuronide (MPAG). The current study was designed to unravel the renal excretory pathway of MPA and MPAG, and their potential drug-drug interactions. The role of multidrug resistance protein (MRP) 2 and MRP4 in MPA disposition was studied using human embryonic kidney 293 (HEK293) cells overexpressing the human transporters, and in isolated, perfused kidneys of Mrp2-deficient rats and Mrp4-deficient mice. Using these models, we identified MPA as substrate of MRP2 and MRP4, whereas its MPAG appeared to be a substrate of MRP2 only. CsA inhibited MPAG transport via MRP2 for 50% at 8 μM (P < 0.05), whereas Tac had no effect. This was confirmed by cell survival assays, showing a 10-fold increase in MPA cytotoxicity (50% reduction in cell survival changed from 12.2 ± 0.3 μM to 1.33 ± 0.01 μM by MPA + CsA; P < 0.001) and in perfused kidneys, showing a 50% reduction in MPAG excretion (P < 0.05). The latter effect was observed in Mrp2-deficient animals as well, supporting the importance of Mrp2 in MPAG excretion. CsA, but not Tac, inhibited MPA glucuronidation by rat kidney homogenate and human uridine 5'-diphospho-glucuronosyltransferase- glucuronosyltransferase 1A9 (P < 0.05 and P < 0.01, respectively). We conclude that MPA is a substrate of both MRP2 and MRP4, but MRP2 is the main transporter involved in renal MPAG excretion. In conclusion, CsA, but not Tac, influences MPA clearance by inhibiting renal MPA glucuronidation and MRP2-mediated MPAG secretion.

AB - Mycophenolic acid (MPA) is an immunosuppressant used in transplant rejection, often in combination with cyclosporine (CsA) and tacrolimus (Tac). The drug is cleared predominantly via the kidneys, and 95% of the administered dose appears in urine as 7-hydroxy mycophenolic acid glucuronide (MPAG). The current study was designed to unravel the renal excretory pathway of MPA and MPAG, and their potential drug-drug interactions. The role of multidrug resistance protein (MRP) 2 and MRP4 in MPA disposition was studied using human embryonic kidney 293 (HEK293) cells overexpressing the human transporters, and in isolated, perfused kidneys of Mrp2-deficient rats and Mrp4-deficient mice. Using these models, we identified MPA as substrate of MRP2 and MRP4, whereas its MPAG appeared to be a substrate of MRP2 only. CsA inhibited MPAG transport via MRP2 for 50% at 8 μM (P < 0.05), whereas Tac had no effect. This was confirmed by cell survival assays, showing a 10-fold increase in MPA cytotoxicity (50% reduction in cell survival changed from 12.2 ± 0.3 μM to 1.33 ± 0.01 μM by MPA + CsA; P < 0.001) and in perfused kidneys, showing a 50% reduction in MPAG excretion (P < 0.05). The latter effect was observed in Mrp2-deficient animals as well, supporting the importance of Mrp2 in MPAG excretion. CsA, but not Tac, inhibited MPA glucuronidation by rat kidney homogenate and human uridine 5'-diphospho-glucuronosyltransferase- glucuronosyltransferase 1A9 (P < 0.05 and P < 0.01, respectively). We conclude that MPA is a substrate of both MRP2 and MRP4, but MRP2 is the main transporter involved in renal MPAG excretion. In conclusion, CsA, but not Tac, influences MPA clearance by inhibiting renal MPA glucuronidation and MRP2-mediated MPAG secretion.

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