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The Role of Organic Anion–Transporting Polypeptides and Their Common Genetic Variants in Mycophenolic Acid Pharmacokinetics
Open accessAbstract
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.
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Treiber, A., Schneiter, R., Häusler, S., & Stieger, B. (2007) · Drug Metabolism and Disposition · doi:10.1124/dmd.106.013615 · Cited by 299
Cited by
Roth, M., Obaidat, A., & Hagenbuch, B. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01724.x · Cited by 767
Shitara, Y., Maeda, K., Ikejiri, K., Yoshida, K., Horie, T., & Sugiyama, Y. (2013) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.1823 · Cited by 418
Clinically and pharmacologically relevant interactions of antidiabetic drugs
May, M., & Schindler, C. (2016) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/2042018816638050 · Cited by 160
Impact of genetic variation in OATP transporters to drug disposition and response
Gong, I. Y., & Kim, R. B. (2013) · Drug Metabolism and Pharmacokinetics · doi:10.2133/dmpk.dmpk-12-rv-099 · Cited by 137
Metadata
- Authors
- Picard, N., Yee, S. W., Woillard, J.-B., Lebranchu, Y., Le Meur, Y., Giacomini, K. M., & Marquet, P.
- Venue
- Clinical Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2009-11-04
- Volume
- 87
- Issue
- 1
- Pages
- 100-108
- ISSN
- 0009-9236 (ISSN-L)
- 1532-6535
- OpenAlex
- W2084774611
- Cited by
- 165
- References
- 1
- FWCI
- 6.12
- Type
- journal article
- Language
- en
- Open access
- green
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- Picard, N., Yee, S. W., Woillard, J.-B., Lebranchu, Y., Le Meur, Y., Giacomini, K. M., & Marquet, P. (2010). The Role of Organic Anion–Transporting Polypeptides and Their Common Genetic Variants in Mycophenolic Acid Pharmacokinetics. Clinical Pharmacology & Therapeutics. https://doi.org/10.1038/clpt.2009.205
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