This document presents an overview of transporters as targets for drugs. Transporters are membrane proteins that control the movement of drugs across biological barriers through various transport mechanisms. There are two main types of transporters - ATP-binding cassette (ABC) transporters and solute carrier (SLC) transporters. ABC transporters use ATP hydrolysis to actively transport substrates while SLC transporters use ion gradients to facilitate transport. Transporters play important roles in pharmacokinetic and pharmacodynamic pathways but can also contribute to drug resistance. Targeting transporters offers opportunities to modulate drug absorption, distribution, and resistance.

1. TRANSPORTERS AS TARGETS
FOR DRUGS
P R E S E N T E D B Y : S H I K H A Y . S I N G H
U N D E R T H E G U I D A N C E O F : D R . K B K O T E S H W A R A
D E P A R T M E N T O F P H A R M A C E U T I C S
R E G I S T R A T I O N N O . 1 6 0 6 1 7 0 0 9
ManipalCollegeofPharmaceuticalSciences(MCOPS)

2. TRANSPORTERS AS TARGETS FOR DRUGS
• INTRODUCTION
• TRANSPORTERS
• TYPES OF TRANSPORTERS
• MEMBRANE TRANSPORT & DRUG RESISTANCE
• PHARMACOKINECTIC PATHWAYS
• CONCLUSION
• REFERENCES
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
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CONTENTS

3. TRANSPORTERS AS TARGETS FOR DRUGS
• WHAT IS BIO-TRANSPORT?
• The movement of drug from one side of the biological barrier to other is called Bio-transport
• The mechanisms involved in transfer of drugs across the biological barrier called Transport
mechanisms
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
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INTRODUCTION
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Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
MECHANISM OF MEMBRANE PERMEATION
TRANSPORTERS AS TARGETS FOR DRUGSManipalCollegeofPharmaceuticalSciences(MCOPS)

5. Transport
Carrier
mediated
Active
primary secondary
Facilitated
Non carrier
mediated
Passive
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INTRODUCTION
……
TRANSPORTERS AS TARGETS FOR DRUGS

6. • Transporters are membrane proteins that are present in all organisms
• These proteins controls
• Drug-transporting proteins operate in
 pharmacokinetic pathways
 pharmacodynamic pathways
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
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TRANSPORTERS
TRANSPORTERS AS TARGETS FOR DRUGS
Efflux of cellular waste, environmental
toxins, & other xenobiotics
Influx of essential nutrients & ions

7. Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
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TYPES OF TRANSPORTERS
• 2000 genes in the human genome (7% of the total number of genes) code for
transporters or transporter-related proteins
• Transporters are of two major superfamilies
TRANSPORTERS AS TARGETS FOR DRUGS
TRANSPORTERS
1.ABC
TRANSPORTERS
1.SLC
TRANSPORTERS

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TRANSPORTERS AS TARGETS FOR DRUGS
TYPES OF TRANSPORTERS….
1. ATP BINDING CASSETTE TRANSPORTERS
• Most ABC proteins are primary active transporters
• 49 known genes for ABC proteins that can be grouped into 7 subclasses from
ABCA to ABCG
• The best recognized in the ABC superfamily are
I. P-glycoprotein (P-gp encoded by ABCB1, also termed MDR1)
II. Cystic fibrosis transmembrane regulator (CFTR)
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
ManipalCollegeofPharmaceuticalSciences(MCOPS)

9. TRANSPORTERS AS TARGETS FOR DRUGS
TYPES OF TRANSPORTERS….
STRUCTURE OF ABC TRANSPORTERS
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
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10. Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
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TRANSPORTERS AS TARGETS FOR DRUGS
TYPES OF TRANSPORTERS….
STRUCTURE OF ABC TRANSPORTERS...
• ABC transporter consist of two distinct domains
Transmembrane domain (TMD)
• Membrane-spanning domain (MSD) or Integral membrane
(IM) domain
• Consists of alpha helices, embedded in the membrane bilayer
Nucleotide-binding domain (NBD)
• Site for ATP binding
• Located in the cytoplasm

11.  EXPORTERS-
N-terminal & C-terminal that are fused as a single polypeptide chain,
Arranged as TMD-NBD-TMD-NBD
 IMPORTERS-
Have an inverted organization i.e NBD-TMD-NBD-TMD
NBD domain is N-terminal whereas TMD is C-terminal
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
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ManipalCollegeofPharmaceuticalSciences(MCOPS) TRANSPORTERS AS TARGETS FOR DRUGS
TYPES OF TRANSPORTERS….
STRUCTURE OF ABC TRANSPORTERS...

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TRANSPORTERS AS TARGETS FOR DRUGS
TYPES OF TRANSPORTERS….
MECHANISM BEHIND ABC TRANSPORTER
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
• As they are Active transporters they require energy in the form of ATP
• Conformational changes in the Transmembrane domain (TMD)

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GENE NAME FAMILY NAME NO. OF
FAMILIES
DISEASE ASSOCIATED
ABCA ABC A 12 Tangiers dis
Stargadts dis
ABCB ABC B 11 PFIHC
ABCC ABC C 13 Cystic fibrosis
Dubin Johnson syndrome
ABCD ABC D 4 Adreno-leukodystrophy
ABCE ABC E 1
ABCF ABC F 3
ABCG ABC G 5 Sitosterolemia
TRANSPORTERS AS TARGETS FOR DRUGS
TYPES OF TRANSPORTERS….
TYPE OF ABC TRANSPORTERS
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
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14. 1. Alternating-access model
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TYPES OF TRANSPORTERS….
ABC TRANSPORTER MODEL
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics

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2. ATP-Switch model
TRANSPORTERS AS TARGETS FOR DRUGS
TYPES OF TRANSPORTERS….
ABC TRANSPORTER MODEL...
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics

16. Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
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ANTICANCER DRUG:
•P-glycoprotein is overexpressed in tumor cells after exposure to cytotoxic
anticancer agents
•P-glycoprotein pumps out the anticancer drugs
•Competitive & allosteric agents are used to inhibit p-gp
TRANSPORTERS AS TARGETS FOR DRUGS
TYPES OF TRANSPORTERS….
ABC TRANSPORTER EXAMPLE

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TRANSPORTERS AS TARGETS FOR DRUGS
TYPES OF TRANSPORTERS….
2. SOLUTE CARRIER TRANSPORTERS
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
• 48 SLC families with 315 transporters have been identified in the human genome
• SLC subfamily includes
1. Facilitated transporters
2. Ion-coupled secondary active transporters
• It Contain hydrophobic transmembrane alpha helices
• Many serve as drug targets or in drug absorption and disposition
• Most members of the SLC group are located in the cell membrane
• Widely recognized SLC transporters include the serotonin & dopamine transporters
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18. Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
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TRANSPORTERS AS TARGETS FOR DRUGS
TYPES OF TRANSPORTERS….
STRUCTURE OF SLC TRANSPORTERS

19. • Membrane transporters play a critical role in the development of resistance
1. Anticancer drugs
2. Antimicrobial agents
3. Anticonvulsants
• P-glycoprotein is overexpressed in tumor cells after exposure to cytotoxic Anticancer
agents
• The over-expression of MRP4 is associated with resistance to Antiviral nucleoside
analogs
• Tumors arising from tissues where MDR1 is highly expressed show intrinsic resistance
to different Chemotherapeutic agents
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
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MEMBRANE TRANSPORT & DRUG
RESISTANCE
TRANSPORTERS AS TARGETS FOR DRUGS

20. Reversal agents
o 1st Generation- eg cyclosporine, verapamil
o 2nd Generation- eg valspodar, biricodar
o 3rd Generation- eg tariquidar, zosuquidar, laniquidar
Thiomers
o Eg α-Chitosan–thiobutylamidine (chito– TBA)
Nanocarrier drug delivery system
o Liposomes
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MEMBRANE TRANSPORT & DRUG RESISTANCE
TRANSPORTERS AS TARGETS FOR DRUGS
NOVEL APPROACHES TO OVERCOME RESISTANCE
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics

21. Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
21
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TRANSPORTERS INVOLVED IN
PHARMACOKINECTICS
TRANSPORTERS AS TARGETS FOR DRUGS
HEPATIC TRANSPORTERS
1. Organic anion transporters- OATPs
2. Organic cation transporters-
o OCTs & NTCP for cations & bile salts
o Uptake either by facilitated or secondary active mechanisms
3. ABC transporters such as MRP2, MDR1, BCRP, BSEP & MDR2-
o Mediate efflux (excretion) of drugs & their metabolites, bile salts &
phospholipids
o Against concentration gradient from liver to bile
o This primary active transport is driven by ATP

22. Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
22
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TRANSPORTERS INVOLVED IN
PHARMACOKINECTICS
TRANSPORTERS AS TARGETS FOR DRUGS
HEPATIC TRANSPORTERS...

23. 1. HMG-COA Reductase inhibitor-
 Statins are cholesterol-lowering agents that reversibly inhibit HMG-CoA
reductase enzyme
2. Temocapril-
 It is an ACE inhibitor temocaprilat & is excreted both in bile & urine whereas
other ACEI’s are excreted mainly via the kidney
3. Irinotecan (CPT-11)-
 It is a potent anticancer drug in late-onset it causes gastrointestinal toxic effects
but after IV administration then excreted into the bile by MRP2
4. Troglitazone
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TRANSPORTERS INVOLVED IN
PHARMACOKINECTICS
TRANSPORTERS AS TARGETS FOR DRUGS
DRUGS THAT ACT ON HEPATIC TRANSPORTERS
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics

24. Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
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TRANSPORTERS INVOLVED IN
PHARMACOKINECTICS
TRANSPORTERS AS TARGETS FOR DRUGS
RENAL TRANSPORTERS

25. • Transporters assigned to the apical membrane are in the SLC 22 family
• OCT family involves the uptake of a variety of organic cations
• Drugs that act on OCT are dopamine, choline, N-methylnicotinamide & cimetidine,
ranitidine, metformin, procainamide, and N-acetylprocainamide
• OAT family involves the uptake of a variety of organic anions
• Primary function of organic anion transporters is the removal of xenobiotics include
weak acidic drugs e.g. pravastatin, captopril, pencillins & toxins
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of Pharmaceutics
25
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TRANSPORTERS INVOLVED IN
PHARMACOKINECTICS
TRANSPORTERS AS TARGETS FOR DRUGS
RENAL TRANSPORTERS

26.  Transporters are needed
To regulate bioavailability
To act as drug targets
To eliminate toxins
To overcome resistance
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of
Pharmaceutics 26
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CONCLUSION
TRANSPORTERS AS TARGETS FOR DRUGS

27. 1. Laurence L. B, Bruce A. C, Bjorn C.K, Goodman & Gillman's The Pharmacological
Basis of Therapeutics, McGraw Hill Education; 12 edition (2011), pp.no: 41-70
2. Cooper.G.M, Hausman .E.R (2009), Transport of small molecules, The cell a
molecular approach (fifth edition) , Boston, Sinauer associates, pp.no: 540-571
3. Tortora.G.J, Derrickson. B (2009), Transport across the plasma membrane,
Principles of anatomy and physiology(twelth edition), John wiley and sons, pp.no:
56-72
4. Rang H & Dale M. (2012). Rang and Dale's pharmacology. Elsevier/ Churchill
Livingstone, Edinburgh, pp.294-304
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REFERENCES
TRANSPORTERS AS TARGETS FOR DRUGS
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of
Pharmaceutics

28. ANY QUERIES???
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ManipalCollegeofPharmaceuticalSciences(MCOPS) TRANSPORTERS AS TARGETS FOR DRUGS
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of
Pharmaceutics

29. 29
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My sincere thanks to all my respected professors of MCOPS and my
special thanks to Dr. K B Koteshwara sir; without his guidance I would
not be able to put up my presentation to you.
-Shikha Singh (Ist year Mpharm-Industrial Pharmacy)
TRANSPORTERS AS TARGETS FOR DRUGS
Presented by SHIKHA Y SINGH; under the guidance of Dr. K B Koteshwara.; MCOPS-Department of
Pharmaceutics