P glycoprotein is an efflux transporter that pumps certain drugs and toxins out of cells. It is expressed in the liver, kidneys, intestines and blood brain barrier, protecting tissues from harmful substances. P glycoprotein is a 170 kDa membrane protein composed of two symmetrical halves that contain transmembrane and ATP binding domains. It transports substrates by undergoing conformational changes upon ATP hydrolysis. P glycoprotein contributes to multi-drug resistance in cancer and limits oral absorption and brain penetration of many drugs. Genetic polymorphisms and drug interactions involving P glycoprotein inhibition or induction can significantly impact a drug's pharmacokinetics and toxicity.

1. P glycoprotein
Dr. Uma Advani
Assistant Professor Pharmacology
SMS MC Jaipur

2. Learning Objectives
• Introduction
• Cellular localization of P-gp
• Structure of P-gp
• Drug/substrate recognition
• Substrates for P-gp
• Inhibition of P-gp
• Pharmacological relevance
• Pharmacokinetic implications of P-gp
• Conclusion

3. Introduction
• P-glycoproteins are part of a larger family of
efflux transporters
• They appear to have developed as a mechanism
to protect the body from harmful substances
• They transport certain hydrophobic substances in
the following directions
– into the gut
– into urine
– into bile
– out of the brain
– out of the gonads
– out of other organs

4. Contd…
• Considered as apart of the 1st pass metabolism
• P-glycoprotein has also recently been designated
CD(Cluster Differentiation)243.
• In humans, P-glycoprotein is encoded by the
ABCB1(ATP Binding Cassette Subfamily B) gene
• It functionally protects the body against toxic
xenobiotics & drugs by excreting these compound into
the bile, urine & the intestine
• It is also called Hydrophobic vaccum cleaner/flippase:
transporting drug from inner leaflet of plasma
membrane to lipid bilayer to outer leaflet or to
external medium.

5. Cellular localization of MDR1/P-gp
1
•Cancer cells
•In colon, renal & adrenal tumors
2
•Normal tissues
•Certain cells in liver, pancreas, kidney,(entire length duodenum, jejunum,colon &
rectum)
•Biliary canalicular cells , trophoblast in placenta, endothilial cells,astrocytes in brain
3
•Human fetus

6. Structure of P-gp
• It’s a 170 kDa membrane bound protein, long half life
of 24 hrs.
• Composed of 2 symmetrical halves or cassettes, each
of which contains 6 TM( TransMembrane) domains
that are separated by flexible polypeptide loops
• 2 ATP binding domains in the cytosol side also k/a
Nuclear Binding Folds ( NBF).
• Each ATP binding domain contains 3 regions
– Walker A
– Walker B
– Signature C

8. Efflux of substrate/ drug
Drug binds to
the TM binding
domain
Causes
conformational
changes &
reorganization
into compact
domains
Opening of
the central
pore & efflux
of the drug

9. Substrates for P-gp
Categories Example
Anti cancer drugs Actinomycin, cisplatin, danuorubicin,
dactinomycin, paclitaxel, etoposide,
vincristine, vinblastin etc
CVS drugs Statins (atorvastatin & lovastatin),
celiprolol, diltiazem, digioxin, losartan,
quinidine & verapamil
Anti viral drugs Amrenavir, indinavir, saquinavir, nelfinavir
& ritonavir
Antibacterial Erythomycin, rifampicin, sparfloxicin,
levofloxacin
GIT drugs Cimetidine, risperidone, domperidone,
loperamide & odansetron
Others Chloroquine, dexamethasone,
fexofenadine, morphine, phenytoin,
tacrolimus, cyclosporine

10. Antagonists of P-gp
Competitive
inhibition. E.g.
itraconazole,
dex-Verapamil
Blockage of ATP
hydrolysis. E.g.
valsopodar
(derivative of
cyclosporine D)
Interfering with
both hydrolysis
& substrate
recognition. E.g.
cyclosporine A
Allosteric
inhibition. E.g.
trans-flupentixol

11. Pharmacological relevance
(Multi drug resistance)
Anti cancer
drug resistance
Anti epileptic
drug
resistance
Chloroquine
resistance
Opiods
resistance
Anti viral
resistance
Anti
parasitical

12. Anti cancer therapy
• Over expression of MDR 1 gene conferred
resistance to multiple drugs such as vinca
alkoloids(Vincristine,vinblastine),
anthracyclines(Daunorubicin,doxorubicin) &
taxanes(Paclitaxel &Docetaxel).
• Tumors arising from tissues where MDR1/P-gp is
highly expressed show intrinsic resistance to
chemotherapy
• Recent theory suggest that there is intracellular
transfer of P-gp
• Poor brain penetration of drug like imitanib
mesylate(TKI used in CML,GISTs) is due to P-gp

13. Anti cancer contd…
• 4-aryl-1, 4- dihydropyridines & aromatized 4-
arylpyridines have been synthesized to
increase the MDR resistance reversal of
vinblastine are Chemo sensitizers
• Lamellarin D a marine alkaloid developed for
prostate cancer is a newer cytotoxic drug
insensitive to P-gp

14. Others
• Antiepileptics: like Valproate which is substrate for
Pgp results in pharmacoresistant epilepsy,studies
using Pgp inhibitor like tariquidar increased its
effect.
• Antimalarials:
– Mechanism is controversial for Mefloquine &
Artesunate
– Chloroquine resistant plasmodium falciparum strains
– In vitro can be modulated by verapamil & calcium

15. Contd…
• Opiods
– Due to induction of P-gp
– Increase the efflux from brain
• Antiviral
– Over expression of multidrug transporters is the key
mechanism for resistance to protease inhibitors
– Also involved in development of resistance against
antibiotics
– Biricodar & timcodar ( MDR inhibitors) are effective in
when use with antibiotics like fluoroquinolones

16. Biological barrier to xenobiotics
• P-gp protects us from the harmful effects of
xenobiotics & their toxic metabolites
E.g. DDT is an organochlorine pesticides
• Its metabolite p,p-DDE is an environmental
containment accumulates in animals
• Both induce the MDR1/P-gp gene expression
leading to their clearance

17. Pharmacokinetic implications of
P-gp

18. Role of Transporters
• Transporters mediate tissue specific drug
distribution (drug targeting).
• Transporters serve as protective barriers to
organs and cell types.
• P- glycoprotein in blood brain barriers protects
CNS through efflux mechanisms also.
• Relevant transporters to drug response also
control distribution, absorption and
elimination as well.

19. Absorption
• Intestinal Pgp:reduce absorption of various drugs
like protease inhibitors and anti cancer drugs that
are substrates for P-gp,limits their bioavailability
• Both the passive diffusion & the P-gp operate in
opposite directions
• E.g. Bioavailability of digoxin & cyclosporine is
enhanced by inhibitors & reduced by inducers like
Phenytoin & Rifampicin
– Quinidine(Pgp inhibitor): increases the absorption &
plasma concentrations of morphine
– The bioavailability of Saquinavir is reduced with alcohol
due to excessive expression of P-gp

20. Drug distribution
• Blood brain barrier (BBB)
– Protects the brain from the harmful endogenous &
exogenous substances
– P-gp is the key element of BBB
– Limits the central distribution of beneficial drugs. E.g.
TCA’s, risperidone & antiepileptic drugs
– Combined inhibitory effect of P-gp inhibitors like
cyclosporin A, verapamil are useful approach to increase
the drug concentrations
– Parkinson's & Alzheimer's patients have dysfunctional P-
gp in BBB

22. contd…
• Placental barrier
– Extrusion of drugs toxins & thus helps protect the
fetal malformations
– Poor maternal- fetal transfer of Indinavir has been
shown due to P-gp
– Verapamil or quinidine do not inhibit P-gp activity
in term human placenta

23. Metabolism
• It has been postulated that both the CYP3A4
& P-gp acts in concert to limit the
bioavailability of the drug
• They can "set up" or act as "gatekeepers" for
later P450 cytochrome actions
• There is a substantial overlapping of
substrates between CY3A4 & P-gp

24. P-gp inhibition
• Verapamil an inhibitor of metabolizing enzyme
CYP3A4 & P-gp increases the effect of
paclitaxel
• Less potent P-gp inhibitors such as valspodar,
cyclosporin A and ketoconazole had modest
effect on the brain plasma ratios of nelfinavir
• Piperine (component of black pepper) has
shown to inhibit both CY3A4 & P-gp in rodents
& increase the concentration of various drugs

25. P-gp induction
• Both CYP3A4 & P-gp have overlapping inducers in vitro
• A chronic treatment with rifampicin induces expression of
transport proteins & CYP3A4
• Protease inhibitor( ritonavir) & dexamethasone
• Others include
– Phenobarbitone
– Doxorubicin
– Atazanavir
– Prazocin
– Spiranolactone
– St John’s Wort( hypericum perforatum)

26. Drug excretion
• Renal excretion:Modest role in elimination
,expression of Pgp on luminal proximal tubule cells
in kidney pumps out drug into urine.
– Various drug interactions can result
• Digoxin + Clarithromycin
• Digoxin + Verapamil increased levels of digoxin
• Digoxin + cyclosporine
• Pazufloxacin + cyclosporine
• Cimitedine + itraconazole

27. Modulation Pgp by herbal drugs
• St. Johns’ wort
– Commonly used as anti depressant
– Potent inducer of CYP3A4 & P-gp: causes OCP failure &
serotonin syndrome
– Decreases the concentrations of amitriptyline, cyclosporine,
digoxin, fexofenadine, indinavir, metahdone, midazolam etc
• Piperine
– Inhibitor of P-gp & CYP3A4
• Grapefruit
– Inhibitor of P-gp & CYP3A4

28. Polymorphism of P-gp
• Mutations at 2677 & 3435 have been associated
with alterations P g expression & function
• MDR1 polymorphism also effect the drugs
associated with it.E.g. the non linear PK’s with
large inter individual differences of phenytoin
• MDR1 is highly polymorphic ,may effect the entry
of various drugs across the BBB or the placental
barrier leading to accumulation of toxic
substances
• MDR1 polymorphism may have an influence on
the disease activity in cases of RA ,IBS &
colchicine resistance.

29. Drug interactions: Pgp
• Also involved in many drug interactions
• Loperamide sustrate for Pgp which is used over
the counter for diarrhea, if given with Pgp
inhibitor it crosses BBB increase concentration in
brain& results in respiratory depression.
• Dabidatran (Anticoagulant :Direct thrombin
inhibitor) sustrate for Pgp if given with Pgp
inhibitors like verapamil , clarithromycin&
ticagrelor like drugs there will be increase
concentration and haemorrhage.

30. Conclusion
• P-glycoproteins are part of a larger family of efflux
transporters
• They form an important component of the BBB & the
placental barrier
• Have a protective role in preventing the accumulation
of harmful substances within the body
• Have been found to be a cause for the MDR in varous
diseases especially cancers
• Alterations in P-gp can lead to increased susceptibility
for development of certain diseases like Alzheimer's &
Parkinson’s
• Awareness of potential transporter related drug-drug
interaction for safe medication is need of time.

32. References
• Tandon VR, Kapoor B, Bano G, Gupta S et.al; P-
glycoprotein: Pharmacological relevance. IJP
feb 2006; 38:13-24