The role of organic anion-transporting polypeptides and their common genetic variants in mycophenolic acid pharmacokinetics.
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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 ID
- 19890249 [ View in PubMed]
- Abstract
The goal of this study was to determine the roles of the organic anion-transporting polypeptides (OATPs) OATP1A2, OATP1B1, and OATP1B3 and their genetic variants in the pharmacokinetics of the immunosuppressive drug mycophenolate mofetil (MMF). Using OATP-transfected human embryonic kidney (HEK) cells, we measured the uptake of mycophenolic acid (MPA) and its glucuronide (MPAG). MPAG, but not MPA, significantly accumulated in cells expressing OATP1B3 or OATP1B1 (P < 0.05). The pharmacokinetics of both MPA and MPAG were significantly influenced by the OATP1B3 polymorphism 334T>G/699G>A in 70 renal transplant patients receiving combination treatment of MMF with either tacrolimus or sirolimus, but not in 115 patients receiving MMF and cyclosporine. The decrease in dose-normalized (dn) MPA exposure and the concomitant increase in the MPAG/MPA metabolic ratio are consistent with reduced enterohepatic cycling in patients carrying the OATP1B3 334G-699A haplotype. Further studies demonstrated that this variant of OATP1B3 exhibited a reduced maximal velocity (V(max)) in transfected HEK cells, thereby providing functional evidence to support our clinical findings.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Mycophenolate mofetil Solute carrier organic anion transporter family member 1B1 Protein Humans UnknownSubstrateDetails Mycophenolate mofetil Solute carrier organic anion transporter family member 1B3 Protein Humans UnknownSubstrateDetails