Abstract
Objective
We investigated the association between mycophenolic acid (MPA) pharmacokinetics and organic anion-transporting polypeptide (OATP/SLCO)1B1, 1B3, 2B1 and multidrug resistance-association protein 2 (MRP2/ABCC2) genetic polymorphisms and diarrhea.
Methods
Eighty-seven renal allograft recipients were given repeated doses of mycophenolate mofetil every 12 h at a designated time (09:00 and 21:00). The pharmacokinetics of MPA were analyzed on day 28 posttransplantation.
Results
The dose-adjusted area under the cuve (AUC)6–12 of MPA, an estimate of enterohepatic recirculation, was greater in SLCO1B3 T334G GG (or G699A AA) carriers than in TT carriers (or G699A GG) (40 vs. 25 ng·h/mL per milligram, respectively, P = 0.0497). None of the polymorphism of SLCO1B1, SLCO2B1, or ABCC2 C-24T were associated with MPA pharmacokinetics or diarrhea. However, the oral clearance of MPA in recipients having both the SLCO1B3 T334G GG genotype and the ABCC2 C-24T T allele was significantly lower than in patients having both the SLCO1B3 T334G TT and ABCC2 C-24T CC genotypes (0.15 vs. 0.18 L/h per kilogram, respectively, P = 0.0010).
Conclusions
MPA excretion into bile in patients with SLCO1B3 T334G GG (or G699A AA) was higher than in those with T334G TT (or G699A GG), probably resulting in a higher AUC6–12 value of MPA. MPA uptake into hepatocytes and excretion into bile at first pass may be greater in SLCO1B3 T334G GG carriers than in TT carriers. In addition, the ABCC2 C-24T polymorphism also seems to be associated with enhanced enterohepatic circulation of MPA. The SLCO1B3 and ABCC2 transporters rather than uridine diphosphate-glucuronosyltransferase (UGT) may partly affect interindividual variety in plasma MPA concentration.
Similar content being viewed by others
References
Staatz CE, Tett SE (2007) Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet 46:13–58
Bullingham RE, Nicholls AJ, Kamm BR (1998) Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 34:429–455
Kuypers DR, Naesens M, Vermeire S, Vanrenterghem Y (2005) The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients. Clin Pharmacol Ther 78:351–361
Innocenti F, Liu W, Chen P, Desai AA, Das S, Ratain MJ (2005) Haplotypes of variants in the UDP-glucuronosyltransferase 1A9 and 1A1 genes. Pharmacogenet Genomics 15:295–301
Kagaya H, Inoue K, Miura M, Satoh S, Saito M, Tada H, Habuchi T, Suzuki T (2007) Influence of UGT1A8 and UGT2B7 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol 63:279–288
Inoue K, Miura M, Satoh S, Kagaya H, Saito M, Habuchi T, Suzuki T (2007) Influence of UGT1A7 and UGT1A9 intronic I399 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Ther Drug Monit 29:299–304
Konig J, Seithel A, Gradhand U, Fromm MF (2006) Pharmacogenomics of human OATP transporters. Naunyn-Schmiedeberg’s Arch Pharmacol 372:432–443
Briz O, Serrano MA, Maclas RI, Gonzalez-Gallego J, Marin JJ (2003) Role of organic anion-transporting polypeptides, OATP-A, OATP-C and OATP-8, in the human placenta-maternal liver tandem excretory pathway for foetal bilirubin. Biochem J 371:897–905
Konig J, Cui Y, Nies AT, Keppler D (2000) A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol 278:G156–G164
Kobayashi D, Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I (2003) Involvement of human organic anion transporting polypeptide OATP-B (SLC21A9) in pH-dependent transport across intestinal apical membrane. J Pharmacol Exp Ther 306:703–708
Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, Fattinger K, Meier PJ, Hagenbuch B (2001) Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology 120:525–533
Konig J, Cui Y, Nies AT, Keppler D (2000) Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem 275:23161–23168
Schaub TP, Kartenbeck J, Konig J, Spring H, Dorsam J, Staehler G, Storkel S, Thon WF, Keppler D (1999) Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma. J Am Soc Nephrol 10:1159–1169
Naesens M, Kuypers DR, Verbeke K, Vanrenterghem Y (2006) Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation 82:1074–1084
Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y (2005) Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. Clin Pharmacol Ther 78:81–88
Goodwin B, Hodgson E, Liddle C (1999) The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol Pharmacol 56:1329–1339
Geick A, Eichelbaum M, Burk O (2001) Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 276:14581–14587
Kullak-Ublick GA, Stieger B, Meier PJ (2004) Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 126:322–342
Chung JY, Cho JY, Yu KS, Kim JR, Oh DS, Jung HR, Lim KS, Moon KH, Shin SG, Jang IJ (2005) Effect of OATP1B1 (SLCO1B1) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther 78:342–350
Letschert K, Keppler D, Konig J (2004) Mutations in the SLCO1B3 gene affecting the substrate specificity of the hepatocellular uptake transporter OATP1B3 (OATP8). Pharmacogenetics 14:441–452
Nozawa T, Nakajima M, Tamai I, Noda K, Nezu J, Sai Y, Tsuji A, Yokoi T (2002) Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allele frequencies in the Japanese population and functional analysis. J Pharmacol Exp Ther 302:804–813
Hagenbuch B, Meier PJ (2003) The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta 1609:1–18
Mikkaichi T, Suzuki T, Tanemoto M, Ito S, Abe T (2004) The organic anion transporter (OATP) family. Drug Metab Pharmacokinet 19:171–179
Tsujimoto M, Hirata S, Dan Y, Ohtani H, Sawada Y (2006) Polymorphisms and linkage disequilibrium of the OATP8 (OATP1B3) gene in Japanese subjects. Drug Metab Pharmacokinet 21:165–169
Rau T, Erney B, Gores R, Eschenhagen T, Beck J, Langer T (2006) High-dose methotrexate in pediatric acute lymphoblastic leukemia: impact of ABCC2 polymorphisms on plasma concentrations. Clin Pharmacol Ther 80:468–476
Kagaya H, Inoue K, Miura M, Satoh S, Saito M, Tada H, Habuchi T, Suzuki T (2006) Quantification and 24-hour monitoring of mycophenolic acid by high-performance liquid chromatography in Japanese renal transplant recipients. Yakugaku Zasshi 126:1357–1362
Briz O, Romero MR, Martinez-Becerra P, Macias RI, Perez MJ, Jimenez F, San Martin FG, Marin JJ (2006) OATP8/1B3-mediated cotransport of bile acids and glutathione: an export pathway for organic anions from hepatocytes? J Biol Chem 281:30326–30335
Satoh S, Tada H, Murakami M, Tsuchiya N, Li Z, Numakura K, Saito M, Inoue T, Miura M, Hayase Y, Suzuki T, Habuchi T (2006) Circadian pharmacokinetics of mycophenolic Acid and implication of genetic polymorphisms for early clinical events in renal transplant recipients. Transplantation 82:486–493
Wieland E, Shipkova M, Schellhaas U, Schutz E, Niedmann PD, Armstrong VW, Oellerich M (2000) Induction of cytokine release by the acyl glucuronide of mycophenolic acid: a link to side effects? Clin Biochem 33:107–113
Pou L, Brunet M, Cantarell C, Vidal E, Oppenheimer F, Monforte V, Vilardell J, Roman A, Martorell J, Capdevila L (2001) Mycophenolic acid plasma concentrations: influence of comedication. Ther Drug Monit 23:35–38
Fehrenbach T, Cui Y, Faulstich H, Keppler D (2003) Characterization of the transport of the bicyclic peptide phalloidin by human hepatic transport proteins. Naunyn Schmiedebergs Arch Pharmacol 368:415–420
Simonson SG, Raza A, Martin PD, Mitchell PD, Jarcho JA, Brown CD, Windass AS, Schneck DW (2004) Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clin Pharmacol Ther 76:167–177
Hesselink DA, van Hest RM, Mathot RA, Bonthuis F, Weimar W, de Bruin RW, van Gelder T (2005) Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am J Transplant 5:987–994
Cattaneo D, Perico N, Gaspari F, Gotti E, Remuzzi G (2002) Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation. Kidney Int 62:1060–1067
Picard N, Cresteil T, Premaud A, Marquet P (2004) Characterization of a phase 1 metabolite of mycophenolic acid produced by CYP3A4/5. Ther Drug Monit 26:600–608
El-Sankary W, Plant NJ, Gibson GG, Moore DJ (2000) Regulation of the CYP3A4 gene by hydrocortisone and xenobiotics: role of the glucocorticoid and pregnane X receptors. Drug Metab Dispos 28:493–496
Acknowledgments
This work was partly supported by a grant (No.18923015) from the Japan Society for the Promotion of Science, Tokyo, Japan, and Novartis Ciclosporin Pharmaco-Clinical Forum Research Grant 2007, Tokyo, Japan.
Duality of interest
The authors declare that they have no conflict of interest related to the publication of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Miura, M., Satoh, S., Inoue, K. et al. Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol 63, 1161–1169 (2007). https://doi.org/10.1007/s00228-007-0380-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00228-007-0380-7