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Pathway Description
Mycophenolic Acid Metabolism Pathway (old)
Homo sapiens
Drug Metabolism Pathway
Mycophenolic Acid (MPA) is an immunosuppressive agent that acts as a noncompetitive, selective and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). It is available as a prodrug, Mycophenolate mofetil (MMF), which is a 2-morpholinoethyl ester with improved bioavailability. After absorption, MMF is hydrolyzed to MPA and N-(2-carboxymethyl)- morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine by the carboxylesterases CES-1 (in the liver only) and CES-2 (in the liver and intestine). The morpholine metabolites are excreted in the urine. MPA is glucuronidated by UDP glucuronosyl transferases (UGTs) UGT1A7, UGT1A8, UGT1A9 and UGT1A10 to MPA-7-O-glucuronide, which is excreted in the urine. Other metabolites of MPA include MPA-acyl glucoronide, which is formed by UGT2B7, and 6-O-desmethyl-MPA, which is formed by the CYP enzymes CYP3A4, CYP3A5 and CYP2C8. MPA enters hepatocytes by the organic anion transport proteins (OATPs) SLCO1B1 and SLCO1B3. MPA and its metabolites are excreted in the bile via the ABCC2, ABCG2, and ABCB1 proteins.
References
Mycophenolic Acid Pathway (old) References
[PharmgKB](http://www.pharmgkb.org/pathway/PA165964832)
Miura M, Kagaya H, Satoh S, Inoue K, Saito M, Habuchi T, Suzuki T: Influence of drug transporters and UGT polymorphisms on pharmacokinetics of phenolic glucuronide metabolite of mycophenolic acid in Japanese renal transplant recipients. Ther Drug Monit. 2008 Oct;30(5):559-64. doi: 10.1097/FTD.0b013e3181838063.
Pubmed: 18695635
Naesens M, Kuypers DR, Verbeke K, Vanrenterghem Y: Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation. 2006 Oct 27;82(8):1074-84. doi: 10.1097/01.tp.0000235533.29300.e7.
Pubmed: 17060857
Miura M, Satoh S, Inoue K, Kagaya H, Saito M, Inoue T, Suzuki T, Habuchi T: Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol. 2007 Dec;63(12):1161-9. doi: 10.1007/s00228-007-0380-7. Epub 2007 Sep 29.
Pubmed: 17906856
Picard N, Yee SW, Woillard JB, Lebranchu Y, Le Meur Y, Giacomini KM, Marquet P: The role of organic anion-transporting polypeptides and their common genetic variants in mycophenolic acid pharmacokinetics. Clin Pharmacol Ther. 2010 Jan;87(1):100-8. doi: 10.1038/clpt.2009.205. Epub 2009 Nov 4.
Pubmed: 19890249
Michelon H, Konig J, Durrbach A, Quteineh L, Verstuyft C, Furlan V, Ferlicot S, Letierce A, Charpentier B, Fromm MF, Becquemont L: SLCO1B1 genetic polymorphism influences mycophenolic acid tolerance in renal transplant recipients. Pharmacogenomics. 2010 Dec;11(12):1703-13. doi: 10.2217/pgs.10.132.
Pubmed: 21142914
Mackenzie PI: Identification of uridine diphosphate glucuronosyltransferases involved in the metabolism and clearance of mycophenolic acid. Ther Drug Monit. 2000 Feb;22(1):10-3.
Pubmed: 10688250
Mojarrabi B, Mackenzie PI: Characterization of two UDP glucuronosyltransferases that are predominantly expressed in human colon. Biochem Biophys Res Commun. 1998 Jun 29;247(3):704-9. doi: 10.1006/bbrc.1998.8843.
Pubmed: 9647757
Rosso Felipe C, de Sandes TV, Sampaio EL, Park SI, Silva HT Jr, Medina Pestana JO: Clinical impact of polymorphisms of transport proteins and enzymes involved in the metabolism of immunosuppressive drugs. Transplant Proc. 2009 Jun;41(5):1441-55. doi: 10.1016/j.transproceed.2009.03.024.
Pubmed: 19545654
Picard N, Ratanasavanh D, Premaud A, Le Meur Y, Marquet P: Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug Metab Dispos. 2005 Jan;33(1):139-46. doi: 10.1124/dmd.104.001651. Epub 2004 Oct 6.
Pubmed: 15470161
Bernard O, Guillemette C: The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the effects of naturally occurring variants. Drug Metab Dispos. 2004 Aug;32(8):775-8.
Pubmed: 15258099
Fujiyama N, Miura M, Kato S, Sone T, Isobe M, Satoh S: Involvement of carboxylesterase 1 and 2 in the hydrolysis of mycophenolate mofetil. Drug Metab Dispos. 2010 Dec;38(12):2210-7. doi: 10.1124/dmd.110.034249. Epub 2010 Sep 7.
Pubmed: 20823294
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