Skip to main content
SpringerLink
Log in
Book cover

Multi-Drug Resistance in Cancer pp 199–222Cite as

Expression and Function of P-Glycoprotein in Normal Tissues: Effect on Pharmacokinetics

  • Protocol
  • First Online:

Part of the book series: Methods in Molecular Biology ((MIMB,volume 596))

Abstract

ATP-binding cassette (ABC) drug efflux transporters limit intracellular concentration of their substrates by pumping them out of cell through an active, energy dependent mechanism. Several of these proteins have been originally associated with the phenomenon of multidrug resistance; however, later on, they have also been shown to control body disposition of their substrates. P-glycoprotein (Pgp) is the first detected and the best characterized of ABC drug efflux transporters. Apart from tumor cells, its constitutive expression has been reported in a variety of other tissues, such as the intestine, brain, liver, placenta, kidney, and others. Being located on the apical site of the plasma membrane, Pgp can remove a variety of structurally unrelated compounds, including clinically relevant drugs, their metabolites, and conjugates from cells. Driven by energy from ATP, it affects many pharmacokinetic events such as intestinal absorption, brain penetration, transplacental passage, and hepatobiliary excretion of drugs and their metabolites. It is widely believed that Pgp, together with other ABC drug efflux transporters, plays a crucial role in the host detoxication and protection against xenobiotic substances. On the other hand, the presence of these transporters in normal tissues may prevent pharmacotherapeutic agents from reaching their site of action, thus limiting their therapeutic potential. This chapter focuses on P-glycoprotein, its expression, localization, and function in nontumor tissues and the pharmacological consequences hereof.

This is a preview of subscription content, log in via an institution.

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Juliano RL, Ling V (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455:152–162

    CAS  PubMed  Google Scholar 

  2. Bosch I, Croop J (1996) P-glycoprotein multidrug resistance and cancer. Biochim Biophys Acta 1288:F37–F54

    PubMed  Google Scholar 

  3. Goldstein LJ, Gottesman MM, Pastan I (1991) Expression of the MDR1 gene in human cancers. Cancer Treat Res 57:101–119

    CAS  PubMed  Google Scholar 

  4. Kartner N, Riordan JR, Ling V (1983) Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science 221:1285–1288

    CAS  PubMed  Google Scholar 

  5. Schinkel AH, Jonker JW (2003) Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev 55:3–29

    CAS  PubMed  Google Scholar 

  6. Thiebaut F, Tsuruo T, Hamada H et al (1987) Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 84:7735–7738

    CAS  PubMed  Google Scholar 

  7. Fromm MF (2004) Importance of P-glycoprotein at blood–tissue barriers. Trends Pharmacol Sci 25:423–429

    CAS  PubMed  Google Scholar 

  8. Seelig A, Landwojtowicz E (2000) Structure-activity relationship of P-glycoprotein substrates and modifiers. Eur J Pharm Sci 12:31–40

    CAS  PubMed  Google Scholar 

  9. Benet LZ, Cummins CL (2001) The drug efflux-metabolism alliance: biochemical aspects. Adv Drug Deliv Rev 50(Suppl 1):S3–S11

    CAS  PubMed  Google Scholar 

  10. Krishna R, Mayer LD (2000) Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci 11:265–283

    CAS  PubMed  Google Scholar 

  11. Breedveld P, Beijnen JH, Schellens JH (2006) Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs. Trends Pharmacol Sci 27:17–24

    CAS  PubMed  Google Scholar 

  12. Ceckova-Novotna M, Pavek P, Staud F (2006) P-glycoprotein in the placenta: expression, localization, regulation and function. Reprod Toxicol 22:400–410

    CAS  PubMed  Google Scholar 

  13. Lin JH (2003) Drug–drug interaction mediated by inhibition and induction of P-glycoprotein. Adv Drug Deliv Rev 55:53–81

    CAS  PubMed  Google Scholar 

  14. Chen CJ, Clark D, Ueda K et al (1990) Genomic organization of the human multidrug resistance (MDR1) gene and origin of P-glycoproteins. J Biol Chem 265:506–514

    CAS  PubMed  Google Scholar 

  15. Choudhuri S, Klaassen CD (2006) Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int J Toxicol 25:231–259

    CAS  PubMed  Google Scholar 

  16. Callaghan R, Crowley E, Potter S, Kerr ID (2008) P-glycoprotein: so many ways to turn it on. J Clin Pharmacol 48:365–378

    CAS  PubMed  Google Scholar 

  17. Labialle S, Gayet L, Marthinet E, Rigal D, Baggetto LG (2002) Transcriptional regulators of the human multidrug resistance 1 gene: recent views. Biochem Pharmacol 64:943–948

    CAS  PubMed  Google Scholar 

  18. Scotto KW (2003) Transcriptional regulation of ABC drug transporters. Oncogene 22:7496–7511

    CAS  PubMed  Google Scholar 

  19. Umbenhauer DR, Lankas GR, Pippert TR et al (1997) Identification of a P-glycoprotein-deficient subpopulation in the CF-1 mouse strain using a restriction fragment length polymorphism. Toxicol Appl Pharmacol 146:88–94

    CAS  PubMed  Google Scholar 

  20. Hoffmeyer S, Burk O, von Richter O et al (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478

    CAS  PubMed  Google Scholar 

  21. Kimchi-Sarfaty C, Oh JM, Kim IW et al (2007) A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315:525–528

    CAS  PubMed  Google Scholar 

  22. Wang D, Sadee W (2006) Searching for polymorphisms that affect gene expression and mRNA processing: example ABCB1 (MDR1). AAPS J 8:E515–E520

    CAS  PubMed  Google Scholar 

  23. Streetman DS (2007) Clinical pharmacogenetics of the major adenosine triphosphate binding cassette and solute carrier drug transporters. J Pharm Pract 20:219–233

    Google Scholar 

  24. Takano M, Yumoto R, Murakami T (2006) Expression and function of efflux drug transporters in the intestine. Pharmacol Ther 109:137–161

    CAS  PubMed  Google Scholar 

  25. Fojo AT, Ueda K, Slamon DJ et al (1987) Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 84:265–269

    CAS  PubMed  Google Scholar 

  26. Augustijns PF, Bradshaw TP, Gan LS, Hendren RW, Thakker DR (1993) Evidence for a polarized efflux system in CACO-2 cells capable of modulating cyclosporin A transport. Biochem Biophys Res Commun 197:360–365

    CAS  PubMed  Google Scholar 

  27. Burton PS, Conradi RA, Hilgers AR, Ho NF (1993) Evidence for a polarized efflux system for peptides in the apical membrane of Caco-2 cells. Biochem Biophys Res Commun 190:760–766

    CAS  PubMed  Google Scholar 

  28. Hunter J, Hirst BH, Simmons NL (1993) Drug absorption limited by P-glycoprotein-mediated secretory drug transport in human intestinal epithelial Caco-2 cell layers. Pharm Res 10:743–749

    CAS  PubMed  Google Scholar 

  29. Hunter J, Jepson MA, Tsuruo T, Simmons NL, Hirst BH (1993) Functional expression of P-glycoprotein in apical membranes of human intestinal Caco-2 cells. Kinetics of vinblastine secretion and interaction with modulators. J Biol Chem 268:14991–14997

    CAS  PubMed  Google Scholar 

  30. Sparreboom A, van Asperen J, Mayer U et al (1997) Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci USA 94:2031–2035

    CAS  PubMed  Google Scholar 

  31. Meerum Terwogt JM, Malingre MM, Beijnen JH et al (1999) Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. Clin Cancer Res 5:3379–3384

    CAS  PubMed  Google Scholar 

  32. Malingre MM, Richel DJ, Beijnen JH et al (2001) Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. J Clin Oncol 19:1160–1166

    CAS  PubMed  Google Scholar 

  33. Mayer U, Wagenaar E, Beijnen JH et al (1996) Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr 1a P-glycoprotein. Br J Pharmacol 119:1038–1044

    CAS  PubMed  Google Scholar 

  34. Drescher S, Glaeser H, Murdter T et al (2003) P-glycoprotein-mediated intestinal and biliary digoxin transport in humans. Clin Pharmacol Ther 73:223–231

    CAS  PubMed  Google Scholar 

  35. Chiou WL, Chung SM, Wu TC, Ma C (2001) A comprehensive account on the role of efflux transporters in the gastrointestinal absorption of 13 commonly used substrate drugs in humans. Int J Clin Pharmacol Ther 39:93–101

    CAS  PubMed  Google Scholar 

  36. Lin JH, Yamazaki M (2003) Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet 42:59–98

    CAS  PubMed  Google Scholar 

  37. Lown KS, Mayo RR, Leichtman AB et al (1997) Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther 62:248–260

    CAS  PubMed  Google Scholar 

  38. Masuda S, Uemoto S, Hashida T et al (2000) Effect of intestinal P-glycoprotein on daily tacrolimus trough level in a living-donor small bowel recipient. Clin Pharmacol Ther 68:98–103

    CAS  PubMed  Google Scholar 

  39. Benet LZ, Izumi T, Zhang Y, Silverman JA, Wacher VJ (1999) Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery. J Control Release 62:25–31

    CAS  PubMed  Google Scholar 

  40. Wacher VJ, Salphati L, Benet LZ (2001) Active secretion and enterocytic drug metabolism barriers to drug absorption. Adv Drug Deliv Rev 46:89–102

    CAS  PubMed  Google Scholar 

  41. Lin JH, Chiba M, Chen IW et al (1999) Effect of dexamethasone on the intestinal first-pass metabolism of indinavir in rats: evidence of cytochrome P-450 3A (correction of P-450 A) and p-glycoprotein induction. Drug Metab Dispos 27:1187–1193

    CAS  PubMed  Google Scholar 

  42. Loscher W, Potschka H (2005) Blood–brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2:86–98

    PubMed  Google Scholar 

  43. Levin VA (1980) Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 23:682–684

    CAS  PubMed  Google Scholar 

  44. Tsuji A, Tamai I (1997) Blood–brain barrier function of P-glycoprotein. Adv Drug Deliv Rev 25:287–298

    CAS  Google Scholar 

  45. Cordon-Cardo C, O’Brien JP, Casals D et al (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood–brain barrier sites. Proc Natl Acad Sci USA 86:695–698

    CAS  PubMed  Google Scholar 

  46. Thiebaut F, Tsuruo T, Hamada H et al (1989) Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. J Histochem Cytochem 37:159–164

    CAS  PubMed  Google Scholar 

  47. Beaulieu E, Demeule M, Ghitescu L, Beliveau R (1997) P-glycoprotein is strongly expressed in the luminal membranes of the endothelium of blood vessels in the brain. Biochem J 326(Pt 2):539–544

    CAS  PubMed  Google Scholar 

  48. Decleves X, Regina A, Laplanche JL et al (2000) Functional expression of P-glycoprotein and multidrug resistance-associated protein (Mrp1) in primary cultures of rat astrocytes. J Neurosci Res 60:594–601

    CAS  PubMed  Google Scholar 

  49. Pardridge WM, Golden PL, Kang YS, Bickel U (1997) Brain microvascular and astrocyte localization of P-glycoprotein. J Neurochem 68:1278–1285

    CAS  PubMed  Google Scholar 

  50. Lee G, Schlichter L, Bendayan M, Bendayan R (2001) Functional expression of P-glycoprotein in rat brain microglia. J Pharmacol Exp Ther 299:204–212

    CAS  PubMed  Google Scholar 

  51. Tatsuta T, Naito M, Oh-hara T, Sugawara I, Tsuruo T (1992) Functional involvement of P-glycoprotein in blood–brain barrier. J Biol Chem 267:20383–20391

    CAS  PubMed  Google Scholar 

  52. Tsuji A, Terasaki T, Takabatake Y et al (1992) P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells. Life Sci 51:1427–1437

    CAS  PubMed  Google Scholar 

  53. Ohnishi T, Tamai I, Sakanaka K et al (1995) In vivo and in vitro evidence for ATP-dependency of P-glycoprotein-mediated efflux of doxorubicin at the blood–brain barrier. Biochem Pharmacol 49:1541–1544

    CAS  PubMed  Google Scholar 

  54. Schinkel AH (1999) P-Glycoprotein, a gatekeeper in the blood–brain barrier. Adv Drug Deliv Rev 36:179–194

    CAS  PubMed  Google Scholar 

  55. Bartels AL, Kortekaas R, Bart J et al (2008) Blood–brain barrier P-glycoprotein function decreases in specific brain regions with aging: a possible role in progressive neurodegeneration. Neurobiol Aging

    Google Scholar 

  56. Tishler DM, Weinberg KI, Hinton DR et al (1995) MDR1 gene expression in brain of patients with medically intractable epilepsy. Epilepsia 36:1–6

    CAS  PubMed  Google Scholar 

  57. Loscher W (2007) Drug transporters in the epileptic brain. Epilepsia 48(Suppl 1):8–13

    PubMed  Google Scholar 

  58. Sadeque AJ, Wandel C, He H, Shah S, Wood AJ (2000) Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther 68:231–237

    CAS  PubMed  Google Scholar 

  59. Kharasch ED, Hoffer C, Whittington D (2004) The effect of quinidine, used as a probe for the involvement of P-glycoprotein, on the intestinal absorption and pharmacodynamics of methadone. Br J Clin Pharmacol 57:600–610

    CAS  PubMed  Google Scholar 

  60. Troger U, Lins H, Scherrmann JM, Wallesch CW, Bode-Boger SM (2005) Tetraparesis associated with colchicine is probably due to inhibition by verapamil of the P-glycoprotein efflux pump in the blood–brain barrier. BMJ 331:613

    PubMed  Google Scholar 

  61. Enders AC, Blankenship TN (1999) Comparative placental structure. Adv Drug Deliv Rev 38:3–15

    CAS  PubMed  Google Scholar 

  62. van der Aa EM, Peereboom-Stegeman JH, Noordhoek J, Gribnau FW, Russel FG (1998) Mechanisms of drug transfer across the human placenta. Pharm World Sci 20:139–148

    PubMed  Google Scholar 

  63. Audus KL (1999) Controlling drug delivery across the placenta. Eur J Pharm Sci 8:161–165

    CAS  PubMed  Google Scholar 

  64. Pacifici GM, Nottoli R (1995) Placental transfer of drugs administered to the mother. Clin Pharmacokinet 28:235–269

    CAS  PubMed  Google Scholar 

  65. Kalabis GM, Kostaki A, Andrews MH et al (2005) Multidrug resistance phosphoglycoprotein (ABCB1) in the mouse placenta: fetal protection. Biol Reprod 73:591–597

    CAS  PubMed  Google Scholar 

  66. Novotna M, Libra A, Kopecky M et al (2004) P-glycoprotein expression and distribution in the rat placenta during pregnancy. Reprod Toxicol 18:785–792

    CAS  PubMed  Google Scholar 

  67. Sun M, Kingdom J, Baczyk D et al (2006) Expression of the multidrug resistance P-glycoprotein, (ABCB1 glycoprotein) in the human placenta decreases with advancing gestation. Placenta 27:602–609

    CAS  PubMed  Google Scholar 

  68. Gil S, Saura R, Forestier F, Farinotti R (2005) P-glycoprotein expression of the human placenta during pregnancy. Placenta 26:268–270

    CAS  PubMed  Google Scholar 

  69. Nanovskaya TN, Nekhayeva IA, Hankins GD, Ahmed MS (2008) Transfer of methadone across the dually perfused preterm human placental lobule. Am J Obstet Gynecol 198(126):e121–e124

    Google Scholar 

  70. Nakamura Y, Ikeda S, Furukawa T et al (1997) Function of P-glycoprotein expressed in placenta and mole. Biochem Biophys Res Commun 235:849–853

    CAS  PubMed  Google Scholar 

  71. Utoguchi N, Chandorkar GA, Avery M, Audus KL (2000) Functional expression of P-glycoprotein in primary cultures of human cytotrophoblasts and BeWo cells. Reprod Toxicol 14:217–224

    CAS  PubMed  Google Scholar 

  72. Ushigome F, Takanaga H, Matsuo H et al (2000) Human placental transport of vinblastine, vincristine, digoxin and progesterone: contribution of P-glycoprotein. Eur J Pharmacol 408:1–10

    CAS  PubMed  Google Scholar 

  73. Lankas GR, Wise LD, Cartwright ME, Pippert T, Umbenhauer DR (1998) Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reprod Toxicol 12:457–463

    CAS  PubMed  Google Scholar 

  74. Smit JW, Huisman MT, van Tellingen O, Wiltshire HR, Schinkel AH (1999) Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J Clin Invest 104:1441–1447

    CAS  PubMed  Google Scholar 

  75. Huisman MT, Smit JW, Wiltshire HR et al (2001) P-glycoprotein limits oral availability, brain, and fetal penetration of saquinavir even with high doses of ritonavir. Mol Pharmacol 59:806–813

    CAS  PubMed  Google Scholar 

  76. Pavek P, Fendrich Z, Staud F et al (2001) Influence of P-glycoprotein on the transplacental passage of cyclosporine. J Pharm Sci 90:1583–1592

    CAS  PubMed  Google Scholar 

  77. Pavek P, Staud F, Fendrich Z et al (2003) Examination of the functional activity of P-glycoprotein in the rat placental barrier using rhodamine 123. J Pharmacol Exp Ther 305:1239–1250

    CAS  PubMed  Google Scholar 

  78. Holcberg G, Sapir O, Tsadkin M et al (2003) Lack of interaction of digoxin and P-glycoprotein inhibitors, quinidine and verapamil in human placenta in vitro. Eur J Obstet Gynecol Reprod Biol 109:133–137

    CAS  PubMed  Google Scholar 

  79. Sudhakaran S, Ghabrial H, Nation RL et al (2005) Differential bidirectional transfer of indinavir in the isolated perfused human placenta. Antimicrob Agents Chemother 49:1023–1028

    CAS  PubMed  Google Scholar 

  80. Sudhakaran S, Rayner CR, Li J et al (2008) Inhibition of placental P-glycoprotein: impact on indinavir transfer to the foetus. Br J Clin Pharmacol 65:667–673

    CAS  PubMed  Google Scholar 

  81. Molsa M, Heikkinen T, Hakkola J et al (2005) Functional role of P-glycoprotein in the human blood–placental barrier. Clin Pharmacol Ther 78:123–131

    PubMed  Google Scholar 

  82. Rahi M, Heikkinen T, Hakkola J et al (2008) Influence of adenosine triphosphate and ABCB1 (MDR1) genotype on the P-glycoprotein-dependent transfer of saquinavir in the dually perfused human placenta. Hum Exp Toxicol 27:65–71

    CAS  PubMed  Google Scholar 

  83. Nekhayeva IA, Nanovskaya TN, Deshmukh SV et al (2005) Bidirectional transfer of methadone across human placenta. Biochem Pharmacol 69:187–197

    CAS  PubMed  Google Scholar 

  84. Nanovskaya T, Nekhayeva I, Karunaratne N et al (2005) Role of P-glycoprotein in transplacental transfer of methadone. Biochem Pharmacol 69:1869–1878

    CAS  PubMed  Google Scholar 

  85. Nekhayeva IA, Nanovskaya TN, Hankins GD, Ahmed MS (2006) Role of human placental efflux transporter P-glycoprotein in the transfer of buprenorphine, levo-alpha-acetylmethadol, and paclitaxel. Am J Perinatol 23:423–430

    PubMed  Google Scholar 

  86. Kolwankar D, Glover DD, Ware JA, Tracy TS (2005) Expression and function of ABCB1 and ABCG2 in human placental tissue. Drug Metab Dispos 33:524–529

    CAS  PubMed  Google Scholar 

  87. Tanabe M, Ieiri I, Nagata N et al (2001) Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther 297:1137–1143

    CAS  PubMed  Google Scholar 

  88. Hitzl M, Schaeffeler E, Hocher B et al (2004) Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1). Pharmacogenetics 14:309–318

    CAS  PubMed  Google Scholar 

  89. Brown KR (1998) Changes in the use profile of Mectizan: 1987–1997. Ann Trop Med Parasitol 92(Suppl 1):S61–S64

    PubMed  Google Scholar 

  90. Gadducci A, Cosio S, Fanucchi A et al (2003) Chemotherapy with epirubicin and paclitaxel for breast cancer during pregnancy: case report and review of the literature. Anticancer Res 23:5225–5229

    PubMed  Google Scholar 

  91. Kleinman CS, Nehgme RA (2004) Cardiac arrhythmias in the human fetus. Pediatr Cardiol 25:234–251

    CAS  PubMed  Google Scholar 

  92. Oudijk MA, Ruskamp JM, Ambachtsheer BE et al (2002) Drug treatment of fetal tachycardias. Paediatr Drugs 4:49–63

    PubMed  Google Scholar 

  93. Capparelli E, Rakhmanina N, Mirochnick M (2005) Pharmacotherapy of perinatal HIV. Semin Fetal Neonatal Med 10:161–175

    PubMed  Google Scholar 

  94. Clayette P, Jorajuria S, Dormont D (2000) Significance of P-glycoprotein for the pharmacology and clinical use of HIV protease inhibitors. AIDS 14:235–236

    CAS  PubMed  Google Scholar 

  95. Ito S (2001) Transplacental treatment of fetal tachycardia: implications of drug transporting proteins in placenta. Semin Perinatol 25:196–201

    CAS  PubMed  Google Scholar 

  96. Ploen L, Setchell BP (1992) Blood–testis barriers revisited. A homage to Lennart Nicander. Int J Androl 15:1–4

    CAS  PubMed  Google Scholar 

  97. Setchell BP, Main SJ (1978) Drugs and the blood–testis barrier. Environ Health Perspect 24:61–64

    CAS  PubMed  Google Scholar 

  98. Baas F, Borst P (1988) The tissue dependent expression of hamster P-glycoprotein genes. FEBS Lett 229:329–332

    CAS  PubMed  Google Scholar 

  99. Trezise AE, Romano PR, Gill DR et al (1992) The multidrug resistance and cystic fibrosis genes have complementary patterns of epithelial expression. EMBO J 11:4291–4303

    CAS  PubMed  Google Scholar 

  100. Sugawara I, Akiyama S, Scheper RJ, Itoyama S (1997) Lung resistance protein (LRP) expression in human normal tissues in comparison with that of MDR1 and MRP. Cancer Lett 112:23–31

    CAS  PubMed  Google Scholar 

  101. Melaine N, Lienard MO, Dorval I et al (2002) Multidrug resistance genes and p-glycoprotein in the testis of the rat, mouse, Guinea pig, and human. Biol Reprod 67:1699–1707

    CAS  PubMed  Google Scholar 

  102. Lankas GR, Cartwright ME, Umbenhauer D (1997) P-glycoprotein deficiency in a subpopulation of CF-1 mice enhances avermectin-induced neurotoxicity. Toxicol Appl Pharmacol 143:357–365

    CAS  PubMed  Google Scholar 

  103. Hughes CS, Vaden SL, Manaugh CA, Price GS, Hudson LC (1998) Modulation of doxorubicin concentration by cyclosporin A in brain and testicular barrier tissues expressing P-glycoprotein in rats. J Neurooncol 37:45–54

    CAS  PubMed  Google Scholar 

  104. Choo EF, Leake B, Wandel C et al (2000) Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos 28:655–660

    CAS  PubMed  Google Scholar 

  105. Choo EF, Kurnik D, Muszkat M et al (2006) Differential in vivo sensitivity to inhibition of P-glycoprotein located in lymphocytes, testes, and the blood–brain barrier. J Pharmacol Exp Ther 317:1012–1018

    CAS  PubMed  Google Scholar 

  106. Kreuser ED, Hetzel WD, Billia DO, Thiel E (1990) Gonadal toxicity following cancer therapy in adults: significance, diagnosis, prevention and treatment. Cancer Treat Rev 17:169–175

    CAS  PubMed  Google Scholar 

  107. Viviani S, Santoro A, Ragni G et al (1985) Gonadal toxicity after combination chemotherapy for Hodgkin’s disease. Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol 21:601–605

    CAS  PubMed  Google Scholar 

  108. Sharpe RM (1993) Declining sperm counts in men – is there an endocrine cause? J Endocrinol 136:357–360

    CAS  PubMed  Google Scholar 

  109. Sharpe RM, Fisher JS, Millar MM, Jobling S, Sumpter JP (1995) Gestational and lactational exposure of rats to xenoestrogens results in reduced testicular size and sperm production. Environ Health Perspect 103:1136–1143

    CAS  PubMed  Google Scholar 

  110. Roberts MS, Magnusson BM, Burczynski FJ, Weiss M (2002) Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet 41:751–790

    CAS  PubMed  Google Scholar 

  111. Kojima T, Yamamoto T, Murata M et al (2003) Regulation of the blood–biliary barrier: interaction between gap and tight junctions in hepatocytes. Med Electron Microsc 36:157–164

    PubMed  Google Scholar 

  112. Kamimoto Y, Gatmaitan Z, Hsu J, Arias IM (1989) The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles. J Biol Chem 264:11693–11698

    CAS  PubMed  Google Scholar 

  113. Watanabe T, Miyauchi S, Sawada Y et al (1992) Kinetic analysis of hepatobiliary transport of vincristine in perfused rat liver. Possible roles of P-glycoprotein in biliary excretion of vincristine. J Hepatol 16:77–88

    CAS  PubMed  Google Scholar 

  114. Schinkel AH, Mayer U, Wagenaar E et al (1997) Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA 94:4028–4033

    CAS  PubMed  Google Scholar 

  115. Meier Y, Pauli-Magnus C, Zanger UM et al (2006) Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology 44:62–74

    CAS  PubMed  Google Scholar 

  116. Cascorbi I (2006) Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacol Ther 112:457–473

    CAS  PubMed  Google Scholar 

  117. Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75:13–33

    CAS  PubMed  Google Scholar 

  118. Kakumoto M, Takara K, Sakaeda T et al (2002) MDR1-mediated interaction of digoxin with antiarrhythmic or antianginal drugs. Biol Pharm Bull 25:1604–1607

    CAS  PubMed  Google Scholar 

  119. Wakasugi H, Yano I, Ito T et al (1998) Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein. Clin Pharmacol Ther 64:123–128

    CAS  PubMed  Google Scholar 

  120. Boyd RA, Stern RH, Stewart BH et al (2000) Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion. J Clin Pharmacol 40:91–98

    CAS  PubMed  Google Scholar 

  121. Greiner B, Eichelbaum M, Fritz P et al (1999) The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest 104:147–153

    CAS  PubMed  Google Scholar 

  122. Micuda S, Brcakova E, Fuksa L et al (2008) P-glycoprotein function and expression during obstructive cholestasis in rats. Eur J Gastroenterol Hepatol 20:404–412

    CAS  PubMed  Google Scholar 

  123. Zollner G, Fickert P, Silbert D et al (2003) Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol 38:717–727

    CAS  PubMed  Google Scholar 

  124. Zollner G, Wagner M, Fickert P et al (2005) Hepatobiliary transporter expression in human hepatocellular carcinoma. Liver Int 25:367–379

    CAS  PubMed  Google Scholar 

  125. Hidemura K, Zhao YL, Ito K et al (2003) Shiga-like toxin II impairs hepatobiliary transport of doxorubicin in rats by down-regulation of hepatic P glycoprotein and multidrug resistance-associated protein Mrp2. Antimicrob Agents Chemother 47:1636–1642

    CAS  PubMed  Google Scholar 

  126. Pavek P, Dvorak Z (2008) Xenobiotic-induced transcriptional regulation of xenobiotic metabolizing enzymes of the cytochrome P450 superfamily in human extrahepatic tissues. Curr Drug Metab 9:129–143

    CAS  PubMed  Google Scholar 

  127. Lash LH, Putt DA, Cai H (2008) Drug metabolism enzyme expression and activity in primary cultures of human proximal tubular cells. Toxicology 244:56–65

    CAS  PubMed  Google Scholar 

  128. Launay-Vacher V, Izzedine H, Karie S et al (2006) Renal tubular drug transporters. Nephron Physiol 103:p97–p106

    CAS  PubMed  Google Scholar 

  129. Hori R, Okamura N, Aiba T, Tanigawara Y (1993) Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney. J Pharmacol Exp Ther 266:1620–1625

    CAS  PubMed  Google Scholar 

  130. Micuda S, Fuksa L, Mundlova L et al (2007) Morphological and functional changes in p-glycoprotein during dexamethasone-induced hepatomegaly. Clin Exp Pharmacol Physiol 34:296–303

    CAS  PubMed  Google Scholar 

  131. Kawahara M, Sakata A, Miyashita T, Tamai I, Tsuji A (1999) Physiologically based pharmacokinetics of digoxin in mdr1a knockout mice. J Pharm Sci 88:1281–1287

    CAS  PubMed  Google Scholar 

  132. Sasabe H, Kato Y, Suzuki T et al (2004) Differential involvement of multidrug resistance-associated protein 1 and P-glycoprotein in tissue distribution and excretion of grepafloxacin in mice. J Pharmacol Exp Ther 310:648–655

    CAS  PubMed  Google Scholar 

  133. Smit JW, Schinkel AH, Weert B, Meijer DK (1998) Hepatobiliary and intestinal clearance of amphiphilic cationic drugs in mice in which both mdr1a and mdr1b genes have been disrupted. Br J Pharmacol 124:416–424

    CAS  PubMed  Google Scholar 

  134. Angirasa AK, Koch AZ (2002) P-glycoprotein as the mediator of itraconazole–digoxin interaction. J Am Podiatr Med Assoc 92:471–472

    PubMed  Google Scholar 

  135. Rengelshausen J, Goggelmann C, Burhenne J et al (2003) Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin–clarithromycin interaction. Br J Clin Pharmacol 56:32–38

    CAS  PubMed  Google Scholar 

  136. Linnet K, Ejsing TB (2008) A review on the impact of P-glycoprotein on the penetration of drugs into the brain. Eur Neuro­psychopharmacol 18:157–169

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic

    Frantisek Staud, Martina Ceckova, Stanislav Micuda & Petr Pavek

Authors
  1. Frantisek Staud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martina Ceckova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stanislav Micuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Petr Pavek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frantisek Staud .

Editor information

Editors and Affiliations

  1. College of Life Sciences, Nankai University, Weijin Rd. 94, Tianjin, 300071, China, People's Republic

    Jun Zhou

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Humana Press, a part of Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Staud, F., Ceckova, M., Micuda, S., Pavek, P. (2010). Expression and Function of P-Glycoprotein in Normal Tissues: Effect on Pharmacokinetics. In: Zhou, J. (eds) Multi-Drug Resistance in Cancer. Methods in Molecular Biology, vol 596. Humana Press. https://doi.org/10.1007/978-1-60761-416-6_10

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-416-6_10

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60761-415-9

  • Online ISBN: 978-1-60761-416-6

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation