Drug transport and drug targeting

1. GENETIC
POLYMORPHISM
IN
DRUG TRANSPORT
AND
DRUG TARGETS
PREPARED BY :
RUMANA HAMEED
PHARM D
170310820021

2. DRUG TARGETS:
Targeted drug delivery is a method
of delivering medication to a
patient in a manner that increases
the concentration of the
medication in some parts of the
body relative to others.
Objective:
• Provide therapeutic
concentration of drugs at the
site of action
• Reduce systemic toxicity
• Increase patient compliance

3. Classification of Drug
TargetingDrug targeting has been classified into three
types:
First Order
It refers to restricted distribution of the drug-carrier system
to the capillary bed of a predetermined target site, organ
or tissue. Compartmental targeting in lymphatics*,
peritoneal cavity, cerebral ventricles, lungs, joints, eyes,
etc.
Second Order
The selective delivery of drugs to a specific cell type such as
tumor cells and not to the normal cells is referred as
second order drug targeting. The selective drug delivery
to the Kupffer cells in the liver** exemplifies this
approach.
Third Order
The third order targeting is defined as drug delivery

4. Drug Targeting
Passive Targeting Active targeting
Direct local application
Tumor microenvironment
Leaky Vasculature
Antibody targeted
Carbohydrate targeted
Receptor targeted

5. Drug Targeting
Principal schemes of drug targeting currently investigated in various
experimental and clinical settings include:
• Direct application of the drug into the affected zone (organ, tissue)
• Passive accumulation of the drug through leaky vasculature
(tumors, infarcts, inflammation)
• ‘physical’ targeting based on abnormal pH and / or temperature in
the target zone, such as tumor or inflammation (pH- and
temperature-sensitive drug carriers)
• Magnetic targeting of drugs attached to paramagnetic carriers
under the action of external magnetic field
• Use of vector molecules possessing high specific affinity toward the
affected zone

6. The parameters determining the
efficacy of drug targeting:
• Size of the target
• Blood flow through the target
• Number of binding sites for the
targeted drug/ drug carrier within the
target
• Number and affinity of targeting
moieties

7. Passive targeting
approachesPathophysiological factors – Inflammation, Infection, EPR effect
Physicochemical factors – Size, Molecular weight
Anatomical opportunities – Catheterization, Direct injection
Chemical approaches – Prodrugs, Chemical delivery
systems

8. Active targeting
approachesCarrier specificity can be enhanced, through surface
functionalization with site-directed ligands which bind or
interact with specific tissues
Biochemical targets – Organs, Cellular, Organelles,
Intracellular
Physical/External Stimuli – Ultrasound, Magnetic

9. Main Approaches to Targeting
Retrometabolic Systems:
Individual drug molecules chemically
modified to target particularly to the
disease site.
Carrier – Based Systems:
Drug is first packaged non-covalently into
a synthetic Carrier that is then targeted
to the disease site.

10. Drug Targeting:
ProdrugsCompounds that undergo biotransformation
prior to exhibiting pharmacological effect

11. Prodrug Continuing:
Overcoming Barriers
Chemically linking pro-moiety to form prodrug

Biotransformation

Release of parent drug

Barrier is circumvented
Examples:
6-Monoacetylmorphine (6-MAM) is a heroin metabolite which converts into active
morphine in vivo.
Prednisone, a synthetic cortico-steroid drug, is bioactivated by the liver into the active

12. Drug Targeting: Magnetic
Drug Targeting
•Using magnetic nanoparticles (ferrofluids)
• Enhancing efficacy
• Minimum side effects
• Ferromagnetic element (e.g. an implant) is placed in a magnetic field, it
becomes magnetically energized
The Biophysical Targeting
Technique

13. Solid tumor
Apply magnetic
field to concentrate
particles
Modulate field to
release drug from
particles
Inject NMPs IV,
NMP will circulate
through the blood stream
Other options:
1 - Direct injection into
tumor site
2 - Coating NMP with
antibodies to target
Magnetic Drug Targeting Continuing: Guided Drug Delivery
Ability to add
localized heating
combined with drug
delivery

15. Magnetic Drug Targeting Continuing:
Advantages
Magnetic drug targeting is used to treat malignant tumors loco-
regionally without systemic toxicity.
Magnetic particles used as “carrier system” for a variety of
anticancer agents, e.g. radionuclides, cancer – specific antibodies,
and genes
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16. Drug Targeting:
LIPOSOMES
16
These are vesicular concentric structures, range in size from a nanometer to several
micrometers, containing a phospholipids bilayer and are biocompatible, biodegradable and
non immunogenic.
Liposomes have generated a great interest because of their versatility and have played
a significant role in formulation of potent drugs to improve therapeutics. Enhanced
safety and efficacy have been achieved for a wide range of drug classes, including
antitumor agents, antiviral, antimicrobials, vaccines, gene therapeutics etc.

17. Two-
Steps
Targeting
Specifically
binding to
tumor cell
Bind
chromosomal
DNA in target
tumor cell

18. Drug Targeting:
Transdermal
ApproachTransdermal drug delivery system is topically administered
medicaments in the form of patches that deliver drugs for systemic
effects at a predetermined and controlled rate.
A transdermal drug delivery device, which may be of an active or a
passive design, is a device which provides an alternative route for
administering medication. These devices allow for pharmaceuticals
to be delivered across the skin barrier.

19. Transdermal Approach Continuing:
In theory, transdermal patches work very simply. A drug is applied in a
relatively high dosage to the inside of a patch, which is worn on the skin for
an extended period of time. Through a diffusion process, the drug enters the
bloodstream directly through the skin.
Since there is high concentration on the patch and low concentration in the blood, the
drug will keep diffusing into the blood for a long period of time, maintaining the
constant concentration of drug in the blood flow.
19

20. Drug Targeting: Brain targeted drug delivery system
The brain is a delicate organ, and evolution built very efficient ways to protect it.
The delivery of drugs to central nervous system (CNS) is a challenge in the
treatment of neurological disorders.
Drugs may be administered directly into the CNS or administered systematically
(e.g., by intravenous injection) for targeted action in the CNS. The major
challenge to CNS drug delivery is the blood-brain barrier (BBB), which limits
the access of drugs to the brain substance.
Fig: Central Nervous System-selective Estrogens: A Safe Estrogen Therapy
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21. Brain targeted drug delivery system
Continuing:
Advances in understanding of the cell biology of the BBB have
opened new avenues and possibilities for improved drug delivery to
the CNS.
Various strategies that have been used for manipulating the blood-
brain barrier for drug delivery to the brain include osmotic and
chemical opening of the blood-brain barrier as well as the use of
transport/carrier systems.
Other strategies for drug delivery to the brain involve bypassing the
BBB. Various pharmacological agents have been used to open the
BBB and direct invasive methods can introduce therapeutic agents
into the brain substance.
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22. Conclusion
Research related to the development of targeted drug delivery system is
now a day is highly preferred and facilitating field of pharmaceutical
world. It has crossed the infancy period and now touching height of
growths from the pharmacy point of view.
Targeted delivery of drugs, as the name suggests, is to assist the drug
molecule to reach preferably to the desired site. The inherent advantage
of this technique has been the reduction in dose & side effect of the drug.
Overall it may be concluded with the vast database of different studies,
the science of site specific or targeted delivery of these drugs has become
wiser. Manifestation of these strategies in clinical now seems possible in
near future.
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23. Introduction
Transporters are those proteins that carry either
endogenous compounds or xenobiotics across biological
membranes.
They can be classified into either efflux or uptake
proteins, depending on the direction of transport.
The extent of expression of genes coding for transport
proteins can have a profound effect on the bioavailability
and pharmacokinetics of various drugs.
Additionally, genetic variation such as single-nucleotide
polymorphisms (SNPs) of the transport proteins can
cause differences in the uptake or efflux of drugs.

24. In terms of cancer chemotherapy, tumor cells
expressing these proteins can have either enhanced
sensitivity or resistance to various anticancer drugs.
Transporters that serve as efflux pumps on a cell
membrane can remove drugs from the cell before
they can act.
Transport proteins that are responsible for the vital
influx of ions and nutrients such as glucose can
promote growth of tumor cells if overexpressed, or
lead to increased susceptibility for a drug if the
transporter carries that drug into the cell.

25. Importance of Drug
Transporter
Role in overall disposition of drugs to the
target organs
Significant determinant of drug-drug
interaction
Variability in drug response

26. Types of drug
transporter
Two types of transporter :
ATP binding Cassette (ABC) – Found in ABCB,
ABCD and ABCG family. Associated with
multidrug resistance (MDR) of tumor cells
causing treatment failure in cancer.
Solute Carrier (SLC) – Transport varieties of
solute include both charged or uncharged

27. Comparison
ATP Binding Cassette Solute Carrier
Efflux transporter Influx / bidirectional
transporter
Utilize energy from ATP Electrochemical
gradient / facilitated
diffusion
Primary active Secondary active
Subfamilies : ABCA,
ABCB, ABCD, ABCE,
ABCDF, ABCG
Subfamilies ; SLC15,
SLC22, SLCO

28. P-glycoprotein
• ATP binding cassette sub family B member-
1 (ABCB 1)
• Multidrug resistance protein 1 (MDR1)
• Transport various molecules, including
xenobiotic, across cell membrane
• Extensively distributed and expressed
throughout the body

29. Function of P-glycoprotein
Site of transportation Function
Liver – Bile Elimination
Kidney - Urine Excretion
Placenta – Maternal blood Protect fetal from drug
exposure
Intestine – Intestinal lumen Reduce drug absorption into
the blood
Brain – Blood Monitor drug access to the
brain

30. Mechanism of P-
glycoprotein
① Substrate bind to P-gp form the inner
leaflet of the membrane
② ATP binds at the inner side of the
protein
③ ATP is hydrolyzed to produce ADP and
energy
④ Substrate is excreted outside the cell

32. Clinical Importance
P-gp is a multidrug resistant protein (MDR)
Role of P-gp is significant in tumor cells.
Expression of P-gp in tumor cells reduces the
accessibility of cytotoxic drugs by eliminating them
in various pathways. Hence, P-gp may act as a
major barrier to effective drug treatments.
Over expression of P-gp in limit the treatment for
cancer, AIDS, Alzheimer’s and epilepsy.

33. References
Dean M, Hamon Y, Chimini G (July 2001). "The human ATP-binding cassette
(ABC) transporter superfamily”
Hediger MA, Romero MF, Peng JB, Rolfs A, Takanaga H, Bruford EA (2004).
"The ABCs of solute carriers: physiological, pathological and therapeutic
implications of human membrane transport proteins: Introduction”
Dean, Michael (2002-11-01). "The Human ATP-Binding Cassette (ABC)
Transporter Superfamily”
Peter N Bennett, Morris J Brown, Pankaj Sharma, 11th Edition (2012).
“Clinical Pharmacology”
Department of Drug Metabolism, Merck Research Laboratories (Nov 2003).
“Clinical relevance of P-glycoprotein in drug therapy”

34. Thank You