Transcript P-Glycoproteins

Dr. Ganna Tolstanova,
Associated Professor of
Dep. of Biochemistry,
ESC “Institute of Biology”
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Introduction
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Structure

Location and functions
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Substrates and inhibitors
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Important interactions

Future trends
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Conclusion
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Transporters are membrane proteins
Control the influx of essential nutrients and
ions and the efflux of cellular waste, toxins and
drugs
Controls cellular homeostasis
Transporters in body
ATP binding cassette
(ABC)
- Primary active transporters
(rely on ATP hydrolysis)
-49 known genes for ABC
proteins (7 families - ABCA
to ABCG)
-P-glycoprotein (P-gp,
encoded by ABCB1, also
termed MDR1)
Solute carrier
(SLC)
- Facilitated transporters and ioncoupled secondary active transporters
(antiport)
- 300 transporters (43 families – SLC1SLC43)
-Drug targets, drug absorption and
disposition
SERT (serotonin transporter, SLC6A4)
DAT (dopamine transporter, SLC6A3)
1) Pharmacokinetic – Absorption, metabolism,
excretion of drugs
1. Located in intestinal, renal, and
hepatic epithelium
2. Selective absorption and
elimination of endogenous
substances and xenobiotics,
including drugs
3. Work in concert with drug
metabolizing enzymes
4. Tissue specific drug distribution
5. Protective barriers to particular
organs and cell types
2) Pharmacodynamics – Target for many drugs
- SERT (SLC6A4), serotonin transporter
- DAT (SLC6A3), dopamine transporter
3) Drug resistance
- Anticancer drugs (BCRP (ABCG2))
- Antiviral agents (MRP4 (ABCC4))
- Most important member of ABC family
- Transmembrane protein coded by MDR-1 gene
- Functions to actively pump a diverse array of
xenobiotics out of the cells in which it is
expressed
- Display a high level of constitutive (basal)
ATPase activity, which is observed in the
absence of added drugs
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
First described in 1976, by JULIANO & LING
in Chinese hamster ovary cells selected in
culture for colchicines resistance
PULLIAM et al. in 1985 discovered the
particular increased penetration of ivermectin
through the BBB resulting in 31-fold higher
concentration of the drug in the brain than in
the plasma in MDR knocked out mice
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MICKISCH et al., 1991, found P-glycoprotein
inhibition due to cyclosporine enhanced
paclitaxel (Taxol) oral bioavailability
Single polypeptide
Two homologous halves
Each contains six
transmembrane domains
and a hydrophilic region
with an ATP-binding
domain
1) Epithelial cells of gastrointestinal tract
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
Influx of essential nutrients and ions and efflux
of cellular waste , drugs etc.
Extensive overlap in the substrate specificities
and tissue localization of P-gp and drug
metabolizing enzyme in the cytochrome P450
(CYP3A4)
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Lead to the hypothesis that these two proteins
work together to protect the body from
absorption of harmful xenobiotics, acting
synergistically in the small intestine
2) Hepatocytes in liver

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Even if drug is absorbed it is expelled into bile,
enters intestine again
Work synergistically with CYP3A4 in liver
3) Renal epithelial cells

Efflux of drugs into tubular lumen, easily
excreted
4) Tissues with barrier function
 Blood brain
 Blood testis
 Blood placenta

limiting entry and accumulation of many drugs
into the brain and contributing to the protective
function of the central nervous system
5) Cancer cells


Highly expressed, leading to efflux of
anticancer agents from cells
Resistance to these agents


Various classes of drugs
Resulting in efflux of drug from body,
lowering their plasma concentration

P-gp induction or inhibition may have a
substantial effect on the pharmacokinetics and
pharmacodynamics of concomitantly
administered drugs that are substrates for this
transporter.
Digoxin
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Absorption reduced due to co-administration
of rifampicin (MDR1 inducer)
Renal excretion retarded due to concurrent
administration of MDR1 inhibitors (verapamil,
quinidine etc.)
Loperamide
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Peripheral opioid for diarrhea, substrate for Pglycoprotein
Co-administration of quinidine (MDR1
inhibitors) has caused marked respiratory
depression
Protease inhibitors
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Ritonavir, Nelfinavir, Indinavir, Saquinavir
substrates for P-glycoprotein
P-gp transport at the intestinal and/or hepatic
level limits the systemic bioavailability
Poor penetration into the brain, testis
Treatment ineffective and development of
resistance faster
Anticancer agents
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MDR1 highly expressed in cancer cells,
rendering resistant to anticancer agents
Reduced bioavailability
Paclitaxel, actinomycin D, vincristine etc.
substrates for P-gp.
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P-gp induction does not have a therapeutic role
till date, P-gp inhibition is an attractive
therapeutic approach to reverse multidrug
resistance
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Strategies to modulate P-gp function are being
pursued actively in oncology reversal of
multidrug resistance in tumours
several newly developed agents that inhibit Pgp function are in phase I-III clinical trials.
e.g. ONT 093
PSC 31665
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Blockage of P-gp may be useful in facilitating
greater intestinal absorption, bioavailability
and penetration of protease inhibitors into HIV
sanctuary sites as well as reduced excretion.
Simplify protease inhibitor-containing
regimens by reducing the oral doses of
protease inhibitors and the frequency at which
they are taken
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MDR1 gene polymorphisms increases
susceptibility to diseases such as Parkinson's
disease, inflammatory bowel disease, multidrug resistant epilepsy and renal carcinoma.
MDR1 induction beneficial ???
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P-glycoprotein encoded by MDR1 gene that
influences drug pharmacokinetic and
Pharmacodynamics
P-gp inhibition is an attractive therapeutic
approach to reverse multidrug resistance
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
Kathleen M. Giacomini and Yuichi Sugiyama
membrane transporters and drug response ;
Goodman and Gilman's, Pharmacological basis
of therapeutics;11;40-65;2005.
Bertram G. Katzung, Introduction, Basic and
clinical pharmacology:11:9-10;2009
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BRADY, J.M. et al., Tissue distribution and
chemical induction of multiple drug resistance
genes in rats; Drug Metabolism and Disposition,
Baltimore; vol.30; 7; 2005.
CUMMINS, C. L. et al. In vivo modulation of
intestinal CYP3A metabolism by P-glycoprotein:
Studies using the rat single-pass intestinal
perfusion model; Journal of Pharmacology and
Experimental Therapeutics, Baltimore; v.305, n.1;
p.306-314; 2006.
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FROMM, M.F. Importance of P-glycoprotein at
blood-tissue barriers; TRENDS in
Pharmacological Sciences; v.25; n.8; p.423-429;
2004.
KHARASCH, E.D. et al. The effect of quinidine,
used as a probe for the involvement of Pglycoprotein, on the intestinal absorption and
pharmacodynamics of methadone. British
Journal of Clinical Pharmacology, Oxford,
v.57; n.5; p.600-610, 2003.
THANK YOU