Research Journal of Pharmacology and Pharmacodynamics

Open Access Open Access  Restricted Access Subscription Access
Open Access Open Access Open Access  Restricted Access Restricted Access Subscription Access

P-Glycoprotein - A Unique Transporter Pump


Affiliations
1 Shri Sarvajanik Pharmacy College, Mehsana, Gujarat, India
2 Shri Sarvajanik Pharmacy College, Mehsana, India
3 L. M. College of Pharmacy, Ahmedabad, India
     

   Subscribe/Renew Journal


P-Glycoprotein (P-gp)/MDR1 is the 170-kDa ABC drug transporter protein. It is a member of the ABC(ATP Binding Cassette)super family.It is involved in limiting the harmful exposure of toxins, drugs, and xenobiotics to the body by extruding them into the gastrointestinal tract, bile and urine. Drugs or substrates can cross into the cell membrane by simple diffusion, filtration, or by specialized transport. The first step in drug efflux is drug recognition by P-gp followed by ATP-binding and subsequent hydrolysis. Finally, the generated energy is utilized to efflux substrate outside the cell membrane through central pore. P-gp acts as a rate limiting step during various stages of pharmacokinetic of drug but mainly on the absorption. Different drugs have different impact on P-gp expression. Some drugs are substrate of p-gp while some are inducers or inhibitors of P-gp. Altered P-gp/MDR1 activity due to induction and/or inhibition can cause drug-drug interactions with altered drug pharmacokinetics and response of drug. P-gpmayshow gender basis differences and so drug effect in individuals.
Subscription Login to verify subscription
User
Notifications
Font Size


  • Chen J, Raymond K.The role of CYP3A4 and p-glycoprotein in food-drug and herb-drug interactions, Australian pharmacist 2006, 25(9), 732-738.

  • Croop JM. P-glycoprotein structure and evolutionary homologies.Cytotechnology 1993,12:1-32.

  • Lincke CR, Broeks A, Plasterk RH, Borst P. The expression of two P-glycoprotein (P-gp) genes in transgenic Caenorhabditis elegans is confined to intestinal cells. EMBO J1993, 12, 1615-1620.

  • Lin JH.Drug-drug interaction mediated by inhibition and induction of P-glycoprotein.Advanced Drug Delivery Reviews 2003, 55, 53-81.

  • Martin C, Berridge G, Higgins CF, Mistry P, Charlton P, Callaghan R. Communication between multiple drug binding sites on P-glycoprotein. Molecular Pharmacology 2000a.58, 624-632.

  • Shilling RA, Venter H, Velamakanni S, Bapna A, Woebking B, Shahi S, Van Veen HW. New light on multidrug binding by an ATP-binding-cassette transporter. Trends in Pharmacology Sciences 2006, 27, 195-203.

  • Loo TW, Bartlett MC, Clarke DM. Simultaneous binding of two different drugs in the binding pocket of the human multidrug resistance P-glycoprotein. J Biol.Chem. 2003a, 278, 39706-39710.

  • Wang RB, Kuo CL, Lien LL, Lien EJ. Structure-activity relationship: Analyses of p-glycoprotein substrates and inhibitors. JClin. Pharm. Ther.2003, 28, 203-228.

  • Sonveaux N, Vigano C, Shapiro AB, Ling V, Ruysschaert JM. Ligand-mediated tertiary structure changes of reconstituted P-glycoprotein. J Biol. Chem. 1999, 274, 17649-17654.

  • Zhou SF.Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition, Xenobiotica 2008. 38(7-8): 802-832.

  • Romsicki Y, Sharom F. The ATPase and ATP-binding functions of P-glycoprotein modulation by interaction with defined phospholipids. Eur J Biochem 1998, 256, 170-178.

  • Buxbaum E. Co-operating ATP sites in the multiple drug resistance transporter Mdr1. Eur J Biochem 1999, 265, 54-63.

  • Ambudkar SV, Dey S, Hrycyna. Biochemical, cellular and pharmacological aspects of multidrug transporter. Annu Rev Pharmacol Toxicol 1999, 39,361-98.

  • Ueda K, Taguchi Y, Morishima M. How does P-glycoprotein recognize its substrates? Semin Cancer Biol 1997.8, 151-9.

  • Tandon V, Kapoor B.Bano G, Gupta S, Gillani Z, Gupta S, Kour D.P-glycoprotein: pharmacological relevance. Indian J Pharmacol 2006, 38(1),13-24.

  • Van Veen HW, Higgins CF,Konings WN. Molecular basis of multidrug transport by ATP-binding cassette transporters: a proposed two-cylinder engine model, J. Mol. Microbiol. Biotechnol 2001, 3, 185-192.

  • Sauna ZE, Ambudkar SV. Evidence for a requirement for ATP hydrolysis at two distinct steps during a single turnover of the catalytic cycle of human P-glycoprotein. ProcNatlAcadSci 2000, 97, 2515-20.

  • Mark FR, Alhaji BK, Richard C, Christopher FH, Robert CF. Three-dimensional structures of the mammalian multidrug resistance P-glycoprotein demonstrates major conformational changes in the transmembrane domains upon nucleotide binding. J BiolChem 2003, 278, 8294-99.

  • Loo TW, Clarke DM. Do drug substrates enter the common drug-binding pocket of P-glycoprotein through "gates"? Biochem Biophys Res Commun 2005, 329, 419-22.

  • Varma MVS, Perumal OP,Panchagnula R. Functional role of P-glycoprotein in limiting peroral drug absorption: optimizing drug delivery.Current Opinion in Chemical Biology 2006, 10, 367-373.

  • Cortes-Selva F, Munoz-Martinez F, Ilias A, Jimenez AI, Varadi A, Gamarro F, et al. Functional expression of a multidrug P-glycoprotein transporter of Leishmania. BiochemBiophys Res Commun 2005, 329, 502-7.

  • Hayashi M, Tomita M, Awzu S.Transcellular and paracellular contribution to transport processes in the colorectal route. Adv. Drug Deliv. Rev. 1997, 28, 191-204.

  • Hunter J, Hirst BH. Intestinal secretion of drugs. The role of P-glycoprotein and related drug efflux systems in limiting oral dru absorption. Adv. Drug Del. Rev.1997, 25, 129-157.

  • Evers R, Kool M, Van Deemter L, Janssen H, Calafat J, Oomen LCJM, Paulusma CC, Oude Elferink, RPJ, Baas F, Schinkel AH, Borst P. Drug export activity of the human canalicular multispecific organic anion transporter in polarised kidney MDCK cells expressing cMOAT (MRP2) cDNA. J. Clin. Invest. 1998, 101, 1310-1319.

  • Fromm MF, Kauffman HM, Fritz P, Burk O, Kroemer HK, Warzok RW, Eichelbaum,M, Siegmund W, Schrenk D. The effect of rifampin treatment on intestinal expression of human MRP transporters. Am. J. Pathol. 2000, 157, 1575-1580.

  • Watkins PB. Drug metabolism by cytochromes P450 in the liver and small bowel. Gastrointest. Pharmacol. 1992, 21, 511-526.

  • Seelig A. A general pattern for substrate recognition by P-glycoprotein. Eur. J. Biochem. 1998, 251, 252-261.

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

  • Bain L, McLachlan J, LeBlanc G. Structure-activity relationships for xenobiotic transport substrates and inhibitory ligands of P-glycoprotein. Environmental Health Perspectives 1997, 105, 812-818.

  • Wang RB, Kuo CL, Lien LL, Lien EJ. Structure-activity relationship: Analyses of p-glycoprotein substrates and inhibitors. J. Clin. Pharm. Thera. 2003, 28, 203-228.

  • Raub TJ. P-glycoprotein recognition of substrates and circumvention through rational drug design. Mol.Pharmacol.2006, 3, 3-25.

  • Machado CG, Calado RT,Garcia AB, Falcao RP.Age-related changes of the multidrug resistance P-glycoprotein function in normal human peripheral blood T lymphocytes, Br J. Med. Boil. Research 2003, 36, 1653-1657.

  • Lesliea EM, Deeleyb RG, Coleb PC. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol. Appl. Pharmacol. 2005, 204, 216-237.

  • Dean M.The human ATP-binding cassette (ABC) transporter superfamily. National Center for Biotechnology Information (NCBI) 2002, National library of Medicine, Bethesda, MD, USA.

  • Shiraga K, Sakaguchi K, Senoh T, Ohta T.Modulation of doxorubicin sensitivity by cyclosporine A in hepatocellular carcinoma cells and their doxorubicin-resistant sublines. J. Gastroenterol. Hepatol.2001, 16, 460-466.

  • Chaudhary P, Roninson I. Induction of multidrug resistance in human cells by transient exposure to different chemotherapeutic drugs. J. Natl. Caner. Inst.1993, 85, 632-639.

  • Schuetz EG, Furuya KN,Schuetz JD. "Interindividual Variation in Expression of P-Glycoprotein in Normal Human Liver and Secondary Hepatic Neoplasms," Journal of Pharmacology and ExperimentalTherapeutics 1995, 275(2), 1011-1018.

  • Wolbold R, Klein K, Burk O, et al. "Sex is a Major Determinant of CYP3A4 Expression in Human Liver," Hepatology, 2003, 8(4), 978-988.

  • Rabbaa L, Dautrey S, Colas-Linhart N, et al. "Intestinal Elimination of Ofloxacin Enantiomers in the Rat: Evidence of a Carrier-Mediated Process," Antimicrobial Agents and Chemotherapy 1996, 40(9), 2126-2130.

  • Aminimanizani A, Beringer P, Jelliffe R.Comparative Pharmacokinetics and Pharmacodynamics of the Newer Fluoroquinolone Antibacterials.Clinical Pharmacokinetics 2001, 40(3), 169-187.

  • Carrasco-Portugal MC, Flores-Murrieta FJ. Gender Differences in the Pharmacokinetics of Oral Drugs.Pharmacology and Pharmacy, 2011, 2, 31-41.

  • Benet LZ, Cummins CL. The drug efflux: Metabolism alliance-Biochemical aspects. Adv Drug Deliv Rev 2001, 50, S3-S11.

  • Van Asperen J,Schinkel AH, Beijnen JH, et al. Altered pharmacokinetics of vinblastine in MDR lA P-glycoprotein deficient mice. J Natl Cancer Inst 1996, 88, 994-999.

  • Benet LZ, Cummins CL, Wu CY. Unmasking the dynamic interplay between efflux transporters and metabolic enzymes. Int J Pharm 2004, 277, 3-9.

  • VanAsperen J, van Tellingen O, Tijssen F, et al. Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr la P-glycoprotein. Br J Cancer 1999, 79, 108-113.

  • VanAsperen J, van Tellingen O, Schinkel AH, et al: Comparative pharmacokinetics of vinblastine after a 96-hour continuous infusion in wild type mice and mice lacking mdr la P-glycoprotein. J Pharmacol Exp Ther 1999, 289, 329-333.

  • Schuetz EG, Furuya KN, Scheutz JD.Interindividual variation in expression of P-Glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 1995, 275, 1011-1018.

  • Cummins CL, Wu C, Benet LZ. Sex-related differences in the clearance of cytochrome P450 3A4 substrates may be caused by P-glycoprotein. Clin Pharmacol Ther 2002, 72, 474-489.

  • Yokogawa K, Takahashi M, Tamai I, et al. P-glycoprotein dependent disposition kinetics of tacrolimus: Studies in mdr la knockout mice. Pharm Res 1999, 16, 1213-1218.

  • Meyers PA, Schwartz CL, Krailo M, et al. Gender Differences in p-Glycoprotein: Drug Toxicity and Response, J Clin Oncol 2005, 23, 2004-2011.

  • Chiou WL, Chung SM, Wu, Ta C: Potential role of P-Glycoprotein in affecting hepatic metabolism of drugs. Pharm Res 2000, 17, 903-905.

  • Singh S, Parulekar W, Murray N, et al: Influence of sex on toxicity and treatment outcome in small-cell lung cancer. J Clin Oncol 2005, 23, 850-856.

  • Kando JC, Yonkers KA, Cole JO. "Gender as a Risk Factor for Adverse Events to Medications," Drugs1995, 50(1), 1-6.

  • Warrington JS, Greenblatt DJ, and Moltke LL. The Effect of Age on P-Glycoprotein Expression and Function in the Fischer-344 Rat. The journal of pharmacology and experimental therapeutics 2004, 309(2):730-736.

  • Larsen UL, Olesen LH, Nyvold CG, Eriksen J, Jakobsen P, oestergaard M, Autrup H and Andersen V. Human intestinal P-glycoprotein activity estimated by the model substrate digoxin. Scand J Clin Lab Invest 2007, 67, 123-134.

  • Bauer M, Karch R, Neumann F, Abrahiml A, Kletter K, Mueller M, Langer O. Decreased blood-brain barrier P-glycoprotein function with aging. J Nucl Med. 2009, 50 (2), 606.


Abstract Views: 211

PDF Views: 2




  • P-Glycoprotein - A Unique Transporter Pump

Abstract Views: 211  |  PDF Views: 2

Authors

Manisha D. Patel
Shri Sarvajanik Pharmacy College, Mehsana, Gujarat, India
Jigna S. Shah
Shri Sarvajanik Pharmacy College, Mehsana, India
Parloop A. Bhatt
L. M. College of Pharmacy, Ahmedabad, India

Abstract


P-Glycoprotein (P-gp)/MDR1 is the 170-kDa ABC drug transporter protein. It is a member of the ABC(ATP Binding Cassette)super family.It is involved in limiting the harmful exposure of toxins, drugs, and xenobiotics to the body by extruding them into the gastrointestinal tract, bile and urine. Drugs or substrates can cross into the cell membrane by simple diffusion, filtration, or by specialized transport. The first step in drug efflux is drug recognition by P-gp followed by ATP-binding and subsequent hydrolysis. Finally, the generated energy is utilized to efflux substrate outside the cell membrane through central pore. P-gp acts as a rate limiting step during various stages of pharmacokinetic of drug but mainly on the absorption. Different drugs have different impact on P-gp expression. Some drugs are substrate of p-gp while some are inducers or inhibitors of P-gp. Altered P-gp/MDR1 activity due to induction and/or inhibition can cause drug-drug interactions with altered drug pharmacokinetics and response of drug. P-gpmayshow gender basis differences and so drug effect in individuals.

References