Pharmacogenetic influences on mycophenolate therapy.
Mycophenolic acid (MPA) is a cornerstone immunosuppressant therapy in solid organ transplantation. MPA is metabolized by uridine diphosphate glucuronosyltransferase to inactive 7-O-MPA-glucuronide (MPAG). At least three minor metabolites are also formed, including a pharmacologically active acyl-glucuronide. MPA and MPAG are subject to enterohepatic recirculation. Biliary excretion of MPA/MPAG involves several transporters, including organic anion transporting polypeptides and multidrug resistant protein-2 (MRP-2). MPA metabolites are also excreted via the kidney, at least in part by MRP-2. MPA exerts its immunosuppressive effect through the inhibition of inosine-5-monophosphate dehydrogenase. Several SNPs have been identified in the genes encoding for uridine diphosphate glucuronosyltransferase, organic anion transporting polypeptides, MRP-2 and inosine-5-monophosphate dehydrogenase. This article provides an extensive overview of the known effects of these SNPs on the pharmacokinetics and pharmacodynamics of MPA.
Barraclough
Katherine A
KA
Department of Nephrology, Level 2, ARTS Building, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Qld 4102, Australia. katherine_barraclough@health.qld.gov.au
Lee
Katie J
KJ
Staatz
Christine E
CE
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D016903:Drug Monitoring; D020719:Glucuronides / Q000493:pharmacokinetics; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D019737:Transplants; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020719:Glucuronides; D014453:Glucuronosyltransferase; D007168:IMP Dehydrogenase; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D009173:Mycophenolic Acid; D027361:Organic Anion Transporters; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C000715087:ABCC2 protein, human; C113145:mycophenolic acid glucuronide