By Abdallah Muhammed Youssof, M.sc. Department of pharmaceutics, college of pharmacy, King Saud University

1. Drug Transport Obstacles
Prepared by:
Abdallah M. Youssof
PhD Student, College of
Pharmacy, KSU
ayoussof@ksu.edu.sa

2. 2
“And of Knowledge, you (mankind) have been given only a little.”

3. Content
I. Objectives
II. Introduction
III. Drug Barriers
IV. Physiological Barriers
V. Biochemical Barriers
VI. Chemical and Physicochemical
Barriers
VII. Methods to Overcome Drug Barriers
VIII. Conclusion
IX. Questions
3

4. I. Objectives
By the end of this lecture you will be able to:
1. Realize the impact of drug barriers on the therapeutic
efficacy
2. Identify the main barriers encountered in drug
transport
3. Understand the clinical importance of P-
glycoproteins
4

5. I. Introduction
 From many years researchers and scientists are working a lot on the
drug discovery.
 Many of the potent drugs have been yet discovered but still the
given drug dose not reach the site of action, especially the drugs
given orally because of barriers
present in body and due to drug properties.
 And this problem also persist with biological products like peptides,
proteins etc. 5

6. II. Types of Drug Barriers
6
Barrier
s
PHYSIOLOGICAL
BARRIERS
BIOCHEMICA
L BARRIERS
PHYSICO-
CHEMICAL
PROPERTIES OF
DRUG
CHEMICAL
BARRIERS

7. III. Physiological Barriers
A. Blood Brain Barrier (BBB): is a membrane
that controls the passage of substances from the
blood into the central nervous system.
 It is not an absolute barrier but is a site that is less
permeable to more hydrophilic substances than are
most other areas of the body; (98% of small Mwt
drugs and 100% of large Mwt drugs, mainly
peptides and proteins, developed for CNS
pathologies don’t readily cross the BBB).
 Excludes ionized substances.
7

8. III. Physiological Barriers
B. Intestinal epithelium: is a single cell layer,
largest and most important barrier against the
external environment.
 Weak acids and bases will be absorbed by simple
diffusion to a greater extent in the part of the GI
tract in which they exist in the most lipid-soluble
(non-ionized) form
 Hydrophilic substances will be transported to the
liver by the portal vein.
 Highly hydrophilic substances may be absorbed
through transporters (xenobiotics with similar 8

9. III. Physiological Barriers
C. Blood Ocular Barrier: is a barrier created by
endothelium of capillaries of the retina and iris.
(Barrier to MOST molecules EXCEPT lipophilic
molecules)
N.B. Passage of molecules results in inflammation &
injury
 Example of drugs that can penetrate barrier:
• Antibiotics: Ciprofloxacin – chloramphenicol
• NSAID – SAID
 Example of drugs that can NOT penetrate barrier:
• Fluorescine dye (So, it is used to test integrity of
retinal circulation)
• Drugs that bound to plasma proteins
9

10. III. Physiological Barriers
D. Skin: The physical barrier is mainly
located in the stratum corneum and
consists of protein-enriched cells and lipid
enriched intercellular domains.
10

11. IV. Biochemical Barriers
A. Metabolizing enzymes: In the lumen of stomach, a mixture of
hydrochloric acid and proteolytic pepsins is the first metabolic barrier
and the enzymes of the upper small intestine act as second barrier.
B. Transporter and efflux pump: Substrate can be transported
through the brush border membrane in a carrier-mediated and pH-
dependent manner. P-glycoprotein (P-gp) is a known MRP(multi
resistance protein) that serves as an efflux pump.
11

12. IV. Biochemical Barriers
P-glycoprotein
 Multidrug resistance protein 1 (MDR1)
 Transport various molecules, including xenobiotic, across cell
membrane
 Extensively distributed and expressed throughout the body
12

13. IV. Biochemical Barriers
13
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
Function of P-glycoprotein

14. IV. Biochemical Barriers
 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 limits the treatment for cancer, AIDS,
Alzheimer’s and epilepsy.
14
Clinical Importance of P-glycoprotein

15. IV. Biochemical Barriers
15

16. IV. Biochemical Barriers
16

17. V. Chemical Barriers
Hydrogen Bonding Potential
 A hydrogen bond is the attractive force between the hydrogen
attached to an
electronegative atom of one molecule and an electronegative atom of
a different molecule.
 Hydrogen bonding is a key contributor to the specificity of
intramolecular and
intermolecular interactions in biological system. 17

18. VI. Physicochemical Properties of Drugs
 Physicochemical properties of drug are also important determinants
in the passage of drugs via the para-cellular path.
 The physicochemical properties such as solubility, ionization,
lipophilicity, permeability, etc. are important for determination of
drug action.
18

19. VII. Methods to Overcome Drug Barriers
1.PHYSICAL METHODS
 External stimuli are applied to open the barrier it includes
ultrasound, iontophoresis, stripping etc.
 Ultrasound, microwave or electromagnetic fields that can be used to
open the blood brain barrier.
 Microwave irradiation facilitated central effects of domperidone by
altering the permeability of blood brain barrier and enhancing the
entry of drug into the CNS.
19

20. VII. Methods to Overcome Drug Barriers
1.PHYSICAL METHODS
 Stripping is a technique used to remove stratum corneum by
application of adhesive tape or cyanoacrylate Glue.
 Iontophoresis and electroporation require electrical forces for drug
delivery across stratum corneum.
20

21. VII. Methods to Overcome Drug Barriers
2. CHEMICAL METHOD
 Chemical method involves the use of chemicals to increase the permeability
of the barrier.
 A large number of absorption enhancers have been studied, such as fatty
acids, bile salts, enamine derivatives of phenylglycine, esters, ethers,
salicylates.
 Mostly used blood brain barrier opening practice is via arterial injection of
hyperosmolar solution (e.g. mannitol, arabinose).
 Chemical enhancers for skin include the compounds that interact with the
lipid matrix of the stratum corneum to alter its nanostructure and thereby 21

22. VII. Methods to Overcome Drug Barriers
2. CHEMICAL METHOD
 The most common chemical enhancer is water, which leads to
hydration of the stratum corneum.
 Solvents, such as ethanol, methanol, chloroform and acetone, as well
as detergents increases the permeability of stratum corneum.
22

23. VII. Methods to Overcome Drug Barriers
3. BIOCHEMICAL METHOD
 Biochemical method involves the biological molecule as permeability
enhancer.
 A 45 kDa biological molecule zonula occludens toxin (Zot), an active tight
junction modulator at the blood brain barrier.
 It also permits an enhanced transport of the therapeutic agents doxorubicin
and paclitaxel.
 Magainin, a naturally occurring pore-forming peptide increase skin
permeability by direct interaction with and disruption of stratum corneum 23

24. VII. Methods to Overcome Drug Barriers
4. DRUG DELIVERY BY FORMULATIONS
 COLLODIAL DRUG CARRIERS: include micelles, emulsions, liposomes
and nanoparticles.
 BIODEGREDABLE NANOPARTICLES: formulated from poly (D,L-
lactide-co-glycolide) (PLGA) are used for sustained and targeted
delivery of different agents including plasmid DNA, proteins and
peptides and low weight molecules.
24

25. VII. Methods to Overcome Drug Barriers
4. DRUG DELIVERY BY FORMULATIONS
 LIPOSOMES: Liposomes are small vesicles that are composed of
unilamellar or multilamellar phospholipids bilayers surrounded by
aqueous compartments.
 PRODRUG: The prodrug are used to overcome various barriers which
can hinder drug delivery, including solubility.
25

26. VIII. Conclusions
26
 The absorption of an orally administered drug depends on its passage
through several barriers to deliver drug. The drug can pass either between or
through the cells, depending on its physicochemical properties.
 Overcoming these barriers help in the development of improved drug
delivery systems to treat different diseases conditions.
 Although many challenges exist in transporting the drug from different
barriers, that’s why pharmaceutical scientists and medicinal chemists are
overcoming them with new drug delivery system that enhance drug delivery.

27. V. Questions
27

28. 1. With respect to the BBB, Which of the following is/or true ?
a. Limits the passage of approx. 100% of large molecular weight molecules
b. Excludes ionized substances
c. Active transport is considered
d. All of the above
2. A Method (s) used to overcome the BBB?
a. Ultrasound
b. Microwave irradiation
c. Both a and b
d. Stripping
28

29. 3. For a drug to be passively transported through the GI tract, it requires to be
a. Ionized and hydrophobic
b. Non-ionized and hydrophilic
c. Non-ionized and hydrophobic
d. None of the above
4. All of the following are true about the blood ocular barrier Except,
a. Barrier to most molecules except hydrophilic molecules
b. Barrier to most molecules except lipophilic molecules
c. NSAIDs can penetrate
d. Drugs bound to plasma proteins can not penetrate
29

30. 5. For transdermal drug delivery, which of the following is/are regarded as the major
barrier (s)?
a. Epidermis
b. Stratum corneum
c. Dermis
d. None of the ab
6. A naturally occurring pore-forming peptide increase skin permeability by direct
interaction with and disruption of stratum corneum lipids?
a. Magainin
b. Zonula occludens toxin (Zot)
c. All of the above
d. None of the above
30

31. 7. Mostly used blood brain barrier opening practice is
a. Arterial injection of hyperosmolar solution
b. Injection of mannitol
c. Injection of arabinose
d. All of the above
8. The permeability of skin barrier could be chemically enhanced using
a. Iontophoresis
b. Absorption enhancers such as bile salts
c. Stripping
d. None of the above
31

32. 9. Regarding P-glycoprotein, which of the following is/are correct?
a. Regarded as a Biochemical barrier
b. Known as multidrug resistance protein 1
c. Overexpressed in tumor cells and
d. All of the above
10. Drug delivery barriers could be overcome using advanced formulations such as
a. Prodrugs
b. Colloidal systems
c. Nanoparticles
d. All of the above
32

33. 33

34. 34