Skip to main content
Erschienen in: Wiener Medizinische Wochenschrift 21-22/2014

01.11.2014 | Review

Interplay of drug metabolizing enzymes with cellular transporters

verfasst von: Michaela Böhmdorfer, PhD, Alexandra Maier-Salamon, PhD, Juliane Riha, Mpharm, Stefan Brenner, Mpharm, Martina Höferl, PhD, Univ.-Prof. Dr. Walter Jäger

Erschienen in: Wiener Medizinische Wochenschrift | Ausgabe 21-22/2014

Einloggen, um Zugang zu erhalten

Summary

Many endogenous and xenobiotic substances and their metabolites are substrates for drug metabolizing enzymes and cellular transporters. These proteins may not only contribute to bioavailability of molecules but also to uptake into organs and, consequently, to overall elimination. The coordinated action of uptake transporters, metabolizing enzymes, and efflux pumps, therefore, is a precondition for detoxification and elimination of drugs. As the understanding of the underlying mechanisms is important to predict alterations in drug disposal, adverse drug reactions and, finally, drug–drug interactions, this review illustrates the interplay between selected uptake/efflux transporters and phase I/II metabolizing enzymes.
Literatur
1.
Zurück zum Zitat Li Y, Lu J, Paxton JW. The role of ABC and SLC transporters in the pharmacokinetics of dietary and herbal phytochemicals and their interactions with xenobiotics. Curr Drug Metab. 2012;13:624–39.PubMedCrossRef Li Y, Lu J, Paxton JW. The role of ABC and SLC transporters in the pharmacokinetics of dietary and herbal phytochemicals and their interactions with xenobiotics. Curr Drug Metab. 2012;13:624–39.PubMedCrossRef
2.
Zurück zum Zitat Decleves X, Jacob A, Yousif S, Shawahna R, Potin S, Scherrmann J-M. Interplay of drug metabolizing CYP450 enzymes and ABC transporters in the blood-brain barrier. Curr Drug Metab. 2011;12:732–41.PubMedCrossRef Decleves X, Jacob A, Yousif S, Shawahna R, Potin S, Scherrmann J-M. Interplay of drug metabolizing CYP450 enzymes and ABC transporters in the blood-brain barrier. Curr Drug Metab. 2011;12:732–41.PubMedCrossRef
3.
Zurück zum Zitat Zhang L, Zhang Y, Huang S-M. Scientific and regulatory perspectives on metabolizing enzyme-transporter interplay and its role in drug interactions: challenges in predicting drug interactions. Mol Pharm. 2009;6:1766–74.PubMedCrossRef Zhang L, Zhang Y, Huang S-M. Scientific and regulatory perspectives on metabolizing enzyme-transporter interplay and its role in drug interactions: challenges in predicting drug interactions. Mol Pharm. 2009;6:1766–74.PubMedCrossRef
4.
Zurück zum Zitat Rochat B. Importance of influx and efflux systems and xenobiotic metabolizing enzymes in intratumoral disposition of anticancer agents. Curr Cancer Drug Targets. 2009;9:652–74.PubMedCrossRef Rochat B. Importance of influx and efflux systems and xenobiotic metabolizing enzymes in intratumoral disposition of anticancer agents. Curr Cancer Drug Targets. 2009;9:652–74.PubMedCrossRef
5.
Zurück zum Zitat Christians U, Schmitz V, Haschke M. Functional interactions between P-glycoprotein and CYP3A in drug metabolism. Expert Opin Drug Metab Toxicol. 2005;1:641–54.PubMedCrossRef Christians U, Schmitz V, Haschke M. Functional interactions between P-glycoprotein and CYP3A in drug metabolism. Expert Opin Drug Metab Toxicol. 2005;1:641–54.PubMedCrossRef
6.
Zurück zum Zitat Westlind-Johnsson A, Malmebo S, Johansson A, et al. Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism. Drug Metab Dispos Biol Fate Chem. 2003;31:755–61.PubMedCrossRef Westlind-Johnsson A, Malmebo S, Johansson A, et al. Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism. Drug Metab Dispos Biol Fate Chem. 2003;31:755–61.PubMedCrossRef
7.
Zurück zum Zitat Schuetz JD, Beach DL, Guzelian PS. Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver. Pharmacogenetics. 1994;4:11–20.PubMedCrossRef Schuetz JD, Beach DL, Guzelian PS. Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver. Pharmacogenetics. 1994;4:11–20.PubMedCrossRef
8.
Zurück zum Zitat Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A. 1987;84:7735–8.PubMedCentralPubMedCrossRef Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A. 1987;84:7735–8.PubMedCentralPubMedCrossRef
9.
Zurück zum Zitat Zhang Y, Benet LZ. The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet. 2001;40:159–68.PubMedCrossRef Zhang Y, Benet LZ. The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet. 2001;40:159–68.PubMedCrossRef
10.
Zurück zum Zitat Mouly S, Paine MF. P-glycoprotein increases from proximal to distal regions of human small intestine. Pharm Res. 2003;20:1595–9.PubMedCrossRef Mouly S, Paine MF. P-glycoprotein increases from proximal to distal regions of human small intestine. Pharm Res. 2003;20:1595–9.PubMedCrossRef
11.
Zurück zum Zitat Zhang QY, Dunbar D, Ostrowska A, Zeisloft S, Yang J, Kaminsky LS. Characterization of human small intestinal cytochromes P-450. Drug Metab Dispos Biol Fate Chem. 1999;27:804–9.PubMed Zhang QY, Dunbar D, Ostrowska A, Zeisloft S, Yang J, Kaminsky LS. Characterization of human small intestinal cytochromes P-450. Drug Metab Dispos Biol Fate Chem. 1999;27:804–9.PubMed
12.
Zurück zum Zitat Lown KS, Kolars JC, Thummel KE, et al. Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test. Drug Metab Dispos Biol Fate Chem. 1994;22:947–55.PubMed Lown KS, Kolars JC, Thummel KE, et al. Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test. Drug Metab Dispos Biol Fate Chem. 1994;22:947–55.PubMed
13.
Zurück zum Zitat Lown KS, Mayo RR, Leichtman AB, et al. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther. 1997;62:248–60.PubMedCrossRef Lown KS, Mayo RR, Leichtman AB, et al. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther. 1997;62:248–60.PubMedCrossRef
14.
Zurück zum Zitat Wacher VJ, Silverman JA, Zhang Y, Benet LZ. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci. 1998;87:1322–30.PubMedCrossRef Wacher VJ, Silverman JA, Zhang Y, Benet LZ. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci. 1998;87:1322–30.PubMedCrossRef
15.
Zurück zum Zitat Benet LZ, Cummins CL, Wu CY. Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data. Curr Drug Metab. 2003;4:393–8.PubMedCrossRef Benet LZ, Cummins CL, Wu CY. Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data. Curr Drug Metab. 2003;4:393–8.PubMedCrossRef
16.
Zurück zum Zitat Cummins CL, Jacobsen W, Benet LZ. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J Pharmacol Exp Ther. 2002;300:1036–45.PubMedCrossRef Cummins CL, Jacobsen W, Benet LZ. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J Pharmacol Exp Ther. 2002;300:1036–45.PubMedCrossRef
17.
Zurück zum Zitat Cummins CL, Jacobsen W, Christians U, Benet LZ. CYP3A4-transfected Caco-2 cells as a tool for understanding biochemical absorption barriers: studies with sirolimus and midazolam. J Pharmacol Exp Ther. 2004;308:143–55.PubMedCrossRef Cummins CL, Jacobsen W, Christians U, Benet LZ. CYP3A4-transfected Caco-2 cells as a tool for understanding biochemical absorption barriers: studies with sirolimus and midazolam. J Pharmacol Exp Ther. 2004;308:143–55.PubMedCrossRef
18.
Zurück zum Zitat Wu C-Y, Benet LZ. Disposition of tacrolimus in isolated perfused rat liver: influence of troleandomycin, cyclosporine, and gg918. Drug Metab Dispos Biol Fate Chem. 2003;31:1292–5.PubMedCrossRef Wu C-Y, Benet LZ. Disposition of tacrolimus in isolated perfused rat liver: influence of troleandomycin, cyclosporine, and gg918. Drug Metab Dispos Biol Fate Chem. 2003;31:1292–5.PubMedCrossRef
19.
Zurück zum Zitat Synold TW, Dussault I, Forman BM. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med. 2001;7:584–90.PubMedCrossRef Synold TW, Dussault I, Forman BM. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med. 2001;7:584–90.PubMedCrossRef
20.
Zurück zum Zitat Pal D, Mitra AK. MDR- and CYP3A4-mediated drug-herbal interactions. Life Sci. 2006;78:2131–45.PubMedCrossRef Pal D, Mitra AK. MDR- and CYP3A4-mediated drug-herbal interactions. Life Sci. 2006;78:2131–45.PubMedCrossRef
21.
Zurück zum Zitat Dresser GK, Schwarz UI, Wilkinson GR, Kim RB. Coordinate induction of both cytochrome P4503A and MDR1 by St John’s wort in healthy subjects. Clin Pharmacol Ther. 2003;73:41–50.PubMedCrossRef Dresser GK, Schwarz UI, Wilkinson GR, Kim RB. Coordinate induction of both cytochrome P4503A and MDR1 by St John’s wort in healthy subjects. Clin Pharmacol Ther. 2003;73:41–50.PubMedCrossRef
22.
Zurück zum Zitat Lin JH, Yamazaki M. Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet. 2003;42:59–98.PubMedCrossRef Lin JH, Yamazaki M. Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet. 2003;42:59–98.PubMedCrossRef
23.
Zurück zum Zitat Liedauer R, Svoboda M, Wlcek K, et al. Different expression patterns of organic anion transporting polypeptides in osteosarcomas, bone metastases and aneurysmal bone cysts. Oncol Rep. 2009;22:1485–92.PubMed Liedauer R, Svoboda M, Wlcek K, et al. Different expression patterns of organic anion transporting polypeptides in osteosarcomas, bone metastases and aneurysmal bone cysts. Oncol Rep. 2009;22:1485–92.PubMed
24.
Zurück zum Zitat Svoboda M, Riha J, Wlcek K, Jaeger W, Thalhammer T. Organic anion transporting polypeptides (OATPs): regulation of expression and function. Curr Drug Metab. 2011;12:139–53.PubMedCrossRef Svoboda M, Riha J, Wlcek K, Jaeger W, Thalhammer T. Organic anion transporting polypeptides (OATPs): regulation of expression and function. Curr Drug Metab. 2011;12:139–53.PubMedCrossRef
25.
Zurück zum Zitat Svoboda M, Wlcek K, Taferner B, et al. Expression of organic anion-transporting polypeptides 1B1 and 1B3 in ovarian cancer cells: Relevance for paclitaxel transport. Biomed Pharmacother. 2011;65:417–26.PubMedCrossRef Svoboda M, Wlcek K, Taferner B, et al. Expression of organic anion-transporting polypeptides 1B1 and 1B3 in ovarian cancer cells: Relevance for paclitaxel transport. Biomed Pharmacother. 2011;65:417–26.PubMedCrossRef
26.
Zurück zum Zitat Wlcek K, Svoboda M, Riha J, et al. The analysis of organic anion transporting polypeptide (OATP) mRNA and protein patterns in primary and metastatic liver cancer. Cancer Biol Ther. 2011;11:801–11.PubMedCrossRef Wlcek K, Svoboda M, Riha J, et al. The analysis of organic anion transporting polypeptide (OATP) mRNA and protein patterns in primary and metastatic liver cancer. Cancer Biol Ther. 2011;11:801–11.PubMedCrossRef
27.
Zurück zum Zitat Wlcek K, Svoboda M, Sellner F, Krupitza G, Jaeger W, Thalhammer T. Altered expression of organic anion transporter polypeptide (OATP) genes in human breast carcinoma. Cancer Biol Ther. 2008;7:1450–5.PubMedCrossRef Wlcek K, Svoboda M, Sellner F, Krupitza G, Jaeger W, Thalhammer T. Altered expression of organic anion transporter polypeptide (OATP) genes in human breast carcinoma. Cancer Biol Ther. 2008;7:1450–5.PubMedCrossRef
29.
Zurück zum Zitat Yoo H-D, Lee Y-B. Interplay of pharmacogenetic variations in ABCB1 transporters and cytochrome P450 enzymes. Arch Pharm Res. 2011;34:1817–28.PubMedCrossRef Yoo H-D, Lee Y-B. Interplay of pharmacogenetic variations in ABCB1 transporters and cytochrome P450 enzymes. Arch Pharm Res. 2011;34:1817–28.PubMedCrossRef
30.
Zurück zum Zitat Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflüg Arch Eur J Physiol. 2004;447:653–65.CrossRef Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflüg Arch Eur J Physiol. 2004;447:653–65.CrossRef
31.
Zurück zum Zitat König J, Seithel A, Gradhand U, Fromm MF. Pharmacogenomics of human OATP transporters. Naunyn Schmiedebergs Arch Pharmacol. 2006;372:432–43.PubMedCrossRef König J, Seithel A, Gradhand U, Fromm MF. Pharmacogenomics of human OATP transporters. Naunyn Schmiedebergs Arch Pharmacol. 2006;372:432–43.PubMedCrossRef
32.
Zurück zum Zitat Mück W, Mai I, Fritsche L, et al. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther. 1999;65:251–61.PubMedCrossRef Mück W, Mai I, Fritsche L, et al. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther. 1999;65:251–61.PubMedCrossRef
33.
Zurück zum Zitat Lin JH. Transporter-mediated drug interactions: clinical implications and in vitro assessment. Expert Opin Drug Metab Toxicol. 2007;3:81–92.PubMedCrossRef Lin JH. Transporter-mediated drug interactions: clinical implications and in vitro assessment. Expert Opin Drug Metab Toxicol. 2007;3:81–92.PubMedCrossRef
34.
Zurück zum Zitat Shitara Y, Hirano M, Adachi Y, Itoh T, Sato H, Sugiyama Y. In vitro and in vivo correlation of the inhibitory effect of cyclosporin A on the transporter-mediated hepatic uptake of cerivastatin in rats. Drug Metab Dispos Biol Fate Chem. 2004;32:1468–75.PubMed Shitara Y, Hirano M, Adachi Y, Itoh T, Sato H, Sugiyama Y. In vitro and in vivo correlation of the inhibitory effect of cyclosporin A on the transporter-mediated hepatic uptake of cerivastatin in rats. Drug Metab Dispos Biol Fate Chem. 2004;32:1468–75.PubMed
35.
Zurück zum Zitat Lennernäs H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet. 2003;42:1141–60.PubMedCrossRef Lennernäs H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet. 2003;42:1141–60.PubMedCrossRef
36.
Zurück zum Zitat Kantola T, Kivistö KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther. 1998;64:58–65.PubMedCrossRef Kantola T, Kivistö KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther. 1998;64:58–65.PubMedCrossRef
37.
Zurück zum Zitat Siedlik PH, Olson SC, Yang BB, Stern RH. Erythromycin coadministration increases plasma atorvastatin concentrations. J Clin Pharmacol. 1999;39:501–4.PubMed Siedlik PH, Olson SC, Yang BB, Stern RH. Erythromycin coadministration increases plasma atorvastatin concentrations. J Clin Pharmacol. 1999;39:501–4.PubMed
38.
Zurück zum Zitat Lau YY, Okochi H, Huang Y, Benet LZ. Pharmacokinetics of atorvastatin and its hydroxy metabolites in rats and the effects of concomitant rifampicin single doses: relevance of first-pass effect from hepatic uptake transporters, and intestinal and hepatic metabolism. Drug Metab Dispos Biol Fate Chem. 2006;34:1175–81.PubMedCrossRef Lau YY, Okochi H, Huang Y, Benet LZ. Pharmacokinetics of atorvastatin and its hydroxy metabolites in rats and the effects of concomitant rifampicin single doses: relevance of first-pass effect from hepatic uptake transporters, and intestinal and hepatic metabolism. Drug Metab Dispos Biol Fate Chem. 2006;34:1175–81.PubMedCrossRef
39.
Zurück zum Zitat Kiang TKL, Ensom MHH, Chang TKH. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther. 2005;106:97–132.PubMedCrossRef Kiang TKL, Ensom MHH, Chang TKH. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther. 2005;106:97–132.PubMedCrossRef
40.
Zurück zum Zitat Tsujii H, König J, Rost D, Stöckel B, Leuschner U, Keppler D. Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome. Gastroenterology. 1999;117:653–60.PubMedCrossRef Tsujii H, König J, Rost D, Stöckel B, Leuschner U, Keppler D. Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome. Gastroenterology. 1999;117:653–60.PubMedCrossRef
41.
Zurück zum Zitat Jäger W, Gehring E, Hagenauer B, Aust S, Senderowicz A, Thalhammer T. Biliary excretion of flavopiridol and its glucuronides in the isolated perfused rat liver: role of multidrug resistance protein 2 (Mrp2). Life Sci. 2003;73:2841–54.PubMedCrossRef Jäger W, Gehring E, Hagenauer B, Aust S, Senderowicz A, Thalhammer T. Biliary excretion of flavopiridol and its glucuronides in the isolated perfused rat liver: role of multidrug resistance protein 2 (Mrp2). Life Sci. 2003;73:2841–54.PubMedCrossRef
42.
Zurück zum Zitat Jäger W, Zembsch B, Wolschann P, et al. Metabolism of the anticancer drug flavopiridol, a new inhibitor of cyclin dependent kinases, in rat liver. Life Sci. 1998;62:1861–73.PubMedCrossRef Jäger W, Zembsch B, Wolschann P, et al. Metabolism of the anticancer drug flavopiridol, a new inhibitor of cyclin dependent kinases, in rat liver. Life Sci. 1998;62:1861–73.PubMedCrossRef
43.
Zurück zum Zitat Lush RM, Stinson SF, Senderowicz AM, et al. Flavopiridol pharmacokinetics suggests enterohepatic circulation. Clin Pharmacol Ther. 1997;61:145. Lush RM, Stinson SF, Senderowicz AM, et al. Flavopiridol pharmacokinetics suggests enterohepatic circulation. Clin Pharmacol Ther. 1997;61:145.
44.
Zurück zum Zitat Innocenti F, Stadler WM, Iyer L, Ramírez J, Vokes EE, Ratain MJ. Flavopiridol metabolism in cancer patients is associated with the occurrence of diarrhea. Clin Cancer Res Off J Am Assoc Cancer Res. 2000;6:3400–5. Innocenti F, Stadler WM, Iyer L, Ramírez J, Vokes EE, Ratain MJ. Flavopiridol metabolism in cancer patients is associated with the occurrence of diarrhea. Clin Cancer Res Off J Am Assoc Cancer Res. 2000;6:3400–5.
45.
Zurück zum Zitat Senderowicz AM, Headlee D, Stinson SF, et al. Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J Clin Oncol Off J Am Soc Clin Oncol. 1998;16:2986–99. Senderowicz AM, Headlee D, Stinson SF, et al. Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J Clin Oncol Off J Am Soc Clin Oncol. 1998;16:2986–99.
46.
Zurück zum Zitat Jager W, Winter O, Halper B, et al. Modulation of liver canalicular transport processes by the tyrosine-kinase inhibitor genistein: Implications of genistein metabolism in the rat. Hepatology. 1997;26:1467–76.PubMedCrossRef Jager W, Winter O, Halper B, et al. Modulation of liver canalicular transport processes by the tyrosine-kinase inhibitor genistein: Implications of genistein metabolism in the rat. Hepatology. 1997;26:1467–76.PubMedCrossRef
47.
Zurück zum Zitat Hagenauer B, Salamon A, Thalhammer T, et al. In vitro glucuronidation of the cyclin-dependent kinase inhibitor flavopiridol by rat and human liver microsomes: involvement of UDP-glucuronosyltransferases 1A1 and 1A9. Drug Metab Dispos. 2001;29:407–14.PubMed Hagenauer B, Salamon A, Thalhammer T, et al. In vitro glucuronidation of the cyclin-dependent kinase inhibitor flavopiridol by rat and human liver microsomes: involvement of UDP-glucuronosyltransferases 1A1 and 1A9. Drug Metab Dispos. 2001;29:407–14.PubMed
48.
Zurück zum Zitat Jansen PL, Groothuis GM, Peters WH, Meijer DF. Selective hepatobiliary transport defect for organic anions and neutral steroids in mutant rats with hereditary-conjugated hyperbilirubinemia. Hepatology. 1987;7:71–6.PubMedCrossRef Jansen PL, Groothuis GM, Peters WH, Meijer DF. Selective hepatobiliary transport defect for organic anions and neutral steroids in mutant rats with hereditary-conjugated hyperbilirubinemia. Hepatology. 1987;7:71–6.PubMedCrossRef
49.
Zurück zum Zitat Jansen PL, Peters WH, Lamers WH. Hereditary chronic conjugated hyperbilirubinemia in mutant rats caused by defective hepatic anion transport. Hepatology. 1985;5:573–9.PubMedCrossRef Jansen PL, Peters WH, Lamers WH. Hereditary chronic conjugated hyperbilirubinemia in mutant rats caused by defective hepatic anion transport. Hepatology. 1985;5:573–9.PubMedCrossRef
50.
Zurück zum Zitat Robey RW, Medina-Pérez WY, Nishiyama K, et al. Overexpression of the ATP-binding cassette half-transporter, ABCG2 (Mxr/BCrp/ABCP1), in flavopiridol-resistant human breast cancer cells. Clin Cancer Res Off J Am Assoc Cancer Res. 2001;7:145–52. Robey RW, Medina-Pérez WY, Nishiyama K, et al. Overexpression of the ATP-binding cassette half-transporter, ABCG2 (Mxr/BCrp/ABCP1), in flavopiridol-resistant human breast cancer cells. Clin Cancer Res Off J Am Assoc Cancer Res. 2001;7:145–52.
51.
Zurück zum Zitat Maliepaard M, Scheffer GL, Faneyte IF, et al. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res 2001;61:3458–64.PubMed Maliepaard M, Scheffer GL, Faneyte IF, et al. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res 2001;61:3458–64.PubMed
52.
Zurück zum Zitat Cao J, Stieger B, Meier PJ, Vore M. Expression of rat hepatic multidrug resistance-associated proteins and organic anion transporters in pregnancy. Am J Physiol Gastrointest Liver Physiol. 2002;283:G757–66.PubMed Cao J, Stieger B, Meier PJ, Vore M. Expression of rat hepatic multidrug resistance-associated proteins and organic anion transporters in pregnancy. Am J Physiol Gastrointest Liver Physiol. 2002;283:G757–66.PubMed
53.
Zurück zum Zitat Donner MG, Keppler D. Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver. Hepatology. 2001;34:351–9.PubMedCrossRef Donner MG, Keppler D. Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver. Hepatology. 2001;34:351–9.PubMedCrossRef
54.
Zurück zum Zitat Soroka CJ, Lee JM, Azzaroli F, Boyer JL. Cellular localization and up-regulation of multidrug resistance-associated protein 3 in hepatocytes and cholangiocytes during obstructive cholestasis in rat liver. Hepatology. 2001;33:783–91.PubMedCrossRef Soroka CJ, Lee JM, Azzaroli F, Boyer JL. Cellular localization and up-regulation of multidrug resistance-associated protein 3 in hepatocytes and cholangiocytes during obstructive cholestasis in rat liver. Hepatology. 2001;33:783–91.PubMedCrossRef
55.
Zurück zum Zitat Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 2004;24:2783–840.PubMed Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 2004;24:2783–840.PubMed
56.
Zurück zum Zitat Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006;5:493–506.PubMedCrossRef Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006;5:493–506.PubMedCrossRef
57.
Zurück zum Zitat Pallàs M, Porquet D, Vicente A, Sanfeliu C. Resveratrol: new avenues for a natural compound in neuroprotection. Curr Pharm Des. 2013;19:6726–31.PubMedCrossRef Pallàs M, Porquet D, Vicente A, Sanfeliu C. Resveratrol: new avenues for a natural compound in neuroprotection. Curr Pharm Des. 2013;19:6726–31.PubMedCrossRef
58.
Zurück zum Zitat Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos Biol Fate Chem. 2004;32:1377–82.PubMedCrossRef Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos Biol Fate Chem. 2004;32:1377–82.PubMedCrossRef
59.
Zurück zum Zitat Marier J-F, Vachon P, Gritsas A, Zhang J, Moreau J-P, Ducharme MP. Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model. J Pharmacol Exp Ther. 2002;302:369–73.PubMedCrossRef Marier J-F, Vachon P, Gritsas A, Zhang J, Moreau J-P, Ducharme MP. Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model. J Pharmacol Exp Ther. 2002;302:369–73.PubMedCrossRef
60.
Zurück zum Zitat Burkon A, Somoza V. Quantification of free and protein-bound trans-resveratrol metabolites and identification of trans-resveratrol-C/O-conjugated diglucuronides—two novel resveratrol metabolites in human plasma. Mol Nutr Food Res. 2008;52:549–57.PubMedCrossRef Burkon A, Somoza V. Quantification of free and protein-bound trans-resveratrol metabolites and identification of trans-resveratrol-C/O-conjugated diglucuronides—two novel resveratrol metabolites in human plasma. Mol Nutr Food Res. 2008;52:549–57.PubMedCrossRef
61.
Zurück zum Zitat Patel KR, Brown VA, Jones DJL, et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 2010;70:7392–9.PubMedCentralPubMedCrossRef Patel KR, Brown VA, Jones DJL, et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 2010;70:7392–9.PubMedCentralPubMedCrossRef
62.
Zurück zum Zitat Meng X, Maliakal P, Lu H, Lee M-J, Yang CS. Urinary and plasma levels of resveratrol and quercetin in humans, mice, and rats after ingestion of pure compounds and grape juice. J Agric Food Chem. 2004;52:935–42.PubMedCrossRef Meng X, Maliakal P, Lu H, Lee M-J, Yang CS. Urinary and plasma levels of resveratrol and quercetin in humans, mice, and rats after ingestion of pure compounds and grape juice. J Agric Food Chem. 2004;52:935–42.PubMedCrossRef
63.
Zurück zum Zitat Azorín-Ortuño M, Yáñez-Gascón MJ, Vallejo F, et al. Metabolites and tissue distribution of resveratrol in the pig. Mol Nutr Food Res. 2011;55:1154–68.PubMedCrossRef Azorín-Ortuño M, Yáñez-Gascón MJ, Vallejo F, et al. Metabolites and tissue distribution of resveratrol in the pig. Mol Nutr Food Res. 2011;55:1154–68.PubMedCrossRef
64.
Zurück zum Zitat Maier-Salamon A, Hagenauer B, Reznicek G, Szekeres T, Thalhammer T, Jäger W. Metabolism and disposition of resveratrol in the isolated perfused rat liver: role of Mrp2 in the biliary excretion of glucuronides. J Pharm Sci. 2008;97:1615–28.PubMedCrossRef Maier-Salamon A, Hagenauer B, Reznicek G, Szekeres T, Thalhammer T, Jäger W. Metabolism and disposition of resveratrol in the isolated perfused rat liver: role of Mrp2 in the biliary excretion of glucuronides. J Pharm Sci. 2008;97:1615–28.PubMedCrossRef
65.
Zurück zum Zitat Hagenauer B, Maier-Salamon A, Thalhammer T, Zöllner P, Senderowicz A, Jäger W. Metabolism of UCN-01 in isolated perfused rat liver: role of Mrp2 in the biliary excretion of glucuronides. Oncol Rep. 2004;11:1069–75.PubMed Hagenauer B, Maier-Salamon A, Thalhammer T, Zöllner P, Senderowicz A, Jäger W. Metabolism of UCN-01 in isolated perfused rat liver: role of Mrp2 in the biliary excretion of glucuronides. Oncol Rep. 2004;11:1069–75.PubMed
66.
Zurück zum Zitat Maier-Salamon A, Trauner G, Hiltscher R, et al. Hepatic metabolism and biliary excretion of valerenic acid in isolated perfused rat livers: Role of Mrp2 (ABCC2). J Pharm Sci. 2009;98:3839–49.PubMedCrossRef Maier-Salamon A, Trauner G, Hiltscher R, et al. Hepatic metabolism and biliary excretion of valerenic acid in isolated perfused rat livers: Role of Mrp2 (ABCC2). J Pharm Sci. 2009;98:3839–49.PubMedCrossRef
67.
Zurück zum Zitat Picard N, Prémaud A, Rousseau A, Meur Y Le, Marquet P. A comparison of the effect of ciclosporin and sirolimus on the pharmokinetics of mycophenolate in renal transplant patients. Br J Clin Pharmacol. 2006;62:477–84.PubMedCentralPubMedCrossRef Picard N, Prémaud A, Rousseau A, Meur Y Le, Marquet P. A comparison of the effect of ciclosporin and sirolimus on the pharmokinetics of mycophenolate in renal transplant patients. Br J Clin Pharmacol. 2006;62:477–84.PubMedCentralPubMedCrossRef
68.
Zurück zum Zitat Cattaneo D, Merlini S, Zenoni S, et al. Influence of co-medication with sirolimus or cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2005;5:2937–44.CrossRef Cattaneo D, Merlini S, Zenoni S, et al. Influence of co-medication with sirolimus or cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2005;5:2937–44.CrossRef
69.
Zurück zum Zitat Gelder T van, Klupp J, Barten MJ, Christians U, Morris RE. Comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of mycophenolic acid. Ther Drug Monit. 2001;23:119–28.PubMedCrossRef Gelder T van, Klupp J, Barten MJ, Christians U, Morris RE. Comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of mycophenolic acid. Ther Drug Monit. 2001;23:119–28.PubMedCrossRef
70.
Zurück zum Zitat Hesselink DA, Hest RM van, Mathot RAA, et al. Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2005;5:987–94.CrossRef Hesselink DA, Hest RM van, Mathot RAA, et al. Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2005;5:987–94.CrossRef
71.
Zurück zum Zitat Chu XY, Kato Y, Niinuma K, Sudo KI, Hakusui H, Sugiyama Y. Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J Pharmacol Exp Ther. 1997;281:304–14.PubMed Chu XY, Kato Y, Niinuma K, Sudo KI, Hakusui H, Sugiyama Y. Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J Pharmacol Exp Ther. 1997;281:304–14.PubMed
72.
Zurück zum Zitat Innocenti F, Undevia SD, Chen PX, et al. Pharmacogenetic analysis of interindividual irinotecan (CPT-11) pharmacokinetic (PK) variability: evidence for a functional variant of ABCC2. J Clin Oncol. 2004;22:2010.CrossRef Innocenti F, Undevia SD, Chen PX, et al. Pharmacogenetic analysis of interindividual irinotecan (CPT-11) pharmacokinetic (PK) variability: evidence for a functional variant of ABCC2. J Clin Oncol. 2004;22:2010.CrossRef
73.
Zurück zum Zitat Congiu M, Mashford ML, Slavin JL, Desmond PV. Coordinate regulation of metabolic enzymes and transporters by nuclear transcription factors in human liver disease. J Gastroenterol Hepatol. 2009;24:1038–44.PubMedCrossRef Congiu M, Mashford ML, Slavin JL, Desmond PV. Coordinate regulation of metabolic enzymes and transporters by nuclear transcription factors in human liver disease. J Gastroenterol Hepatol. 2009;24:1038–44.PubMedCrossRef
74.
Zurück zum Zitat Bock KW, Bock-Hennig BS. UDP-glucuronosyltransferases (UGTs): from purification of Ah-receptor-inducible UGT1A6 to coordinate regulation of subsets of CYPs, UGTs, and ABC transporters by nuclear receptors. Drug Metab Rev. 2010;42:6–13.PubMedCrossRef Bock KW, Bock-Hennig BS. UDP-glucuronosyltransferases (UGTs): from purification of Ah-receptor-inducible UGT1A6 to coordinate regulation of subsets of CYPs, UGTs, and ABC transporters by nuclear receptors. Drug Metab Rev. 2010;42:6–13.PubMedCrossRef
75.
Zurück zum Zitat Neve EPA, Artursson P, Ingelman-Sundberg M, Karlgren M. An integrated in vitro model for simultaneous assessment of drug uptake, metabolism, and efflux. Mol Pharm. 2013;10:3152–63.PubMedCrossRef Neve EPA, Artursson P, Ingelman-Sundberg M, Karlgren M. An integrated in vitro model for simultaneous assessment of drug uptake, metabolism, and efflux. Mol Pharm. 2013;10:3152–63.PubMedCrossRef
76.
Zurück zum Zitat Mudra DR, Desino KE, Desai PV. In silico, in vitro and in situ models to assess interplay between CYP3A and P-gp. Curr Drug Metab. 2011;12:750–73.PubMedCrossRef Mudra DR, Desino KE, Desai PV. In silico, in vitro and in situ models to assess interplay between CYP3A and P-gp. Curr Drug Metab. 2011;12:750–73.PubMedCrossRef
Metadaten
Titel
Interplay of drug metabolizing enzymes with cellular transporters
verfasst von
Michaela Böhmdorfer, PhD
Alexandra Maier-Salamon, PhD
Juliane Riha, Mpharm
Stefan Brenner, Mpharm
Martina Höferl, PhD
Univ.-Prof. Dr. Walter Jäger
Publikationsdatum
01.11.2014
Verlag
Springer Vienna
Erschienen in
Wiener Medizinische Wochenschrift / Ausgabe 21-22/2014
Print ISSN: 0043-5341
Elektronische ISSN: 1563-258X
DOI
https://doi.org/10.1007/s10354-014-0301-1

Weitere Artikel der Ausgabe 21-22/2014

Wiener Medizinische Wochenschrift 21-22/2014 Zur Ausgabe