PROSTAGLANDIN GLYCOPROTIEN

1. PRATIK SWARUP DAS
Dept of Pharmaceutics
NIET,Pharmacy Institute,Gr.Noida

2.  Introduction
 Membrane transporters
 Physiological sites
 Cellular localisation
 Mechanism of action
 P gp substrates
 Pgp inhibitors

3.  P-glycoprotein (P-gp) belongs to superfamily of ATP-
binding cassette (ABC) transporters.
 The P-gp is a membrane-bound protein, an energy-
dependent efflux transporter driven by ATP hydrolysis.
 P-gp bind ATP and use the energy to drive the transport
of various molecules across all the cell membranes.
 The P-gp efflux transporter can functionally protect the
body against toxic substances and drugs by excreting
these compounds into bile, urine, and the intestinal
lumen and by preventing their accumulation in brain,
gonads, and placenta.


4.  They are membrane proteins that control influx of
essential nutrients and ions, and the efflux of
cellular waste, environmental toxins.
 They exhibit selectivity, saturability and
competitive inhibition by co-transported
substances.

5.  Although MDR is a multifactorial process,
the main obstacle is the expression of
multidrug-efflux pumps that lowers the
intracellular drug levels.
 P-glycoprotein (P-gp) is the longest
identified efflux pump involved in
membrane transporter.

7.  In liver, P-gp is found exclusively on the
biliary canalicular front of hepatocytes and
on the apical surface of epithelial cells in
small biliary ductules.
 In pancreas, P-gp is found on the apical
surface of the epithelial cells of small
ductules but not larger pancreatic ducts.
 In kidney, P gp is found concentrated on the
apical surface of epithelial cells of the

8.  Both colon and jejunum show high levels of P-
gp on the apical surfaces of superficial
columnar epithelial cells.
 Adrenal gland shows high levels of P-gp,
diffusely distributed on the surface of cells in
both the cortex and medulla.
 Its expression is also detected in specialized
epithelial cells with secretory or excretory
functions, trophoblasts in the placenta, and on
endothelial cells of capillary blood vessels at

9.  Drug / substrate recognition:
Amino acids in TM1 are involved in the formation of a
binding pocket that plays a role in determining the
suitable substrate/drug size for P-gp, whereas Gly
residues in TM2 and TM3 are important in
determining substrate specificity.

10. ATP-binding and subsequent hydrolysis:
 Around 2molecules of ATP are hydrolyzed for every
molecule of the drug transported outside the cell.
 one in the transport of substrate and the other in
effecting conformational changes to reset the pump
for the next catalytic cycle.
 Alternate catalytic cycle of ATP hydrolysis and ADP
release is the rate-limiting step in the catalytic cycle
and the substrates exert their effect by modulating
ADP release.

12. Efflux of substrate/drug through central pore:
 P gp intercepts lipophilic drugs as they
move through the lipid membrane and flips
the drugs from inner leaflets to the outer
leaflet and to extra cellular medium.
 A major reorganization of the TM domains
occurs throughout the entire depth of the
membrane resulting in central pore
formation of 2-3 nm diameter and 5-6 nm
in depth on binding of ATP

13.  Neutral or cationic compounds form the substrates
 Anticancer drugs: Actinomycin, cyclosporine-A,
cisplatin,
 Cardiovascular drugs: Atorvastatin, lovastatin,
digitoxin, losartan,
 Antiviral drugs: amprenavir, indinavir, saquinavir,
nelfinavir, and ritonavir
 Antibacterial agents: erythromycin, rifampin,
sparfloxacin, levofloxacin
 GIT drugs: Cimetidine,domperidone, loperamide
and ondansetron
 Other drugs: Chloroquine, dexamethasone,
morphine, phenytoin

14.  Competitive inhibition: Itroconazole, verapimil
 ATP hydrolysis
 ATP hydrolysis blockage& Competitive inhibition:
cyclosporine A
 Allosteric inhibition: flupenthixol

15.  1st Generation:
◦ Verapamil,
◦ Cyclosporine,
◦ Erythromycin,
◦ Ketoconazole,
◦ Tamoxifen
 2nd Generation:
◦ Biricodar (VX-710)