After completion of the lecture, students will be able to: Describe and distinguish passive diffusion and transporter-mediated passage Distinguish transcellular and paracellular transport Identify membrane and drug factors that control diffusion Distinguish uptake and efflux transporters Understand how transporters affect pharmacokinetics

1. Overview of Movement of Drug
Molecules Across Cell Membrane
DR AWAIS IRSHAD

2. Lecture Objectives
After completion of the lecture, students will be able to:
• Describe and distinguish passive diffusion and transporter-mediated
passage
• Distinguish transcellular and paracellular transport
• Identify membrane and drug factors that control diffusion
• Distinguish uptake and efflux transporters
• Understand how transporters affect pharmacokinetics

3. THE NATURE OF CELL MEMBRANE ACTIONS
1. Systemic drug absorption
2. Extravascular routes
3. Site of drug administration

5. The permeability of a drug at the absorption site into the
systemic circulation is intimately related to the:
 Molecular structure and properties of the drug
 Physical and biochemical properties of the cell
membranes.

6. POINTS OF MEMBRANE PENETRATION IN PHARMACOKINETICS
Drugs must pass one or more membranes during absorption, distribution, metabolism,
excretion, and delivery to the site of action.

7.  Transcellular absorption
 Paracellular drug diffusion
.

8. TRANSCELLULAR & PARACELLULAR DIFFUSION.
Passive diffusion is the most common way that drugs penetrate membranes. They can pass through the
matrix of the cell (transcellular passage) or through the water-filled junctions between adjacent cells
(paracellular transport)

9. CELL - MEMBRANE
Individual epithelial cells are joined together by water-filled junctions. The membranes of the cells consist of
bimolecular layers of lipoproteins. The phosphate polar portion of the phospholipids points toward the outer side of
the membrane, and the lipid component makes up the inner core of the membrane. The apical side of the
membrane points toward the outside, or lumen, and the remaining sides are known as the basolateral sides.

10. VILLI & MICROVILLI IN THE SMALL INTESTINE
The membrane of the small intestine is folded into villi, which are then folded further into microvilli. This
provides the membrane with a very large surface area, ideally suited for the absorption of nutrients and
drugs

11. THEORETICAL PLACEMENTS OF UPTAKE AND EFFLUX TRANSPORTERS IN AN EPITHELIAL CELL MEMBRANE SUCH AS THE INTESTINAL MEMBRANE
E represents an efflux transporter such as permeability glycoprotein (P-gp) or breast cancer-resistance protein (BCRP); U represents an uptake
transporter such as organic anion transporting polypeptide (OATP) or organic cation transporter (OCT).
Uptake transporters on the apical membrane and efflux transporters on the basolateral side promote the retention of drugs in the body.
Uptake transporters on the basolateral side of the membrane and efflux transporters on the apical side promote the removal of drug from the
body.

12. Location of some of the major uptake (U) and efflux (E) transporters involved in drug absorption, metabolism, and
excretion.
Efflux transporters include permeability glycoprotein (P-gp), multidrug resistance-associated protein family
(MRP), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), and multidrug and toxin extrusion
protein (MATE).
Uptake transporters include organic anion transporting polypeptide (OATP), organic anion transporter (OAT),

13. SUMMARY OF INTESTINAL EPITHELIAL TRANSPORTERS
Transporters shown by square and oval shapes demonstrate active and facilitated transporters, respectively.
Names of cloned transporters are shown with square or oval shapes.
In the case of active transporters, arrows in the same direction represent symport of substance and the driving force. Arrows going in the reverse direction mean the
antiport

14. Theories about the cell membrane's structure:
The Lipid Bilayer or Unit Membrane Theory:-
 Proposed by Davson and Danielli (1952)
 Plasma membrane to be composed of two layers of phospholipid
 Hydrophilic “head”
 Hydrophobic “tail”
 lipid-soluble drugs tend to penetrate cell membranes more easily than polar molecules.
 However, the bilayer cell membrane structure does not account for the diffusion of
water, small-molecular-weight molecules such as urea, and certain charged ions.

15. The Fluid Mosaic Model Theory:
 Proposed by Singer and Nicolson (1972)
 Explains the “transcellular diffusion” of polar molecules
 The cell membrane, according to this model, is made up of globular proteins
embedded in a dynamic fluid, lipid bilayer matrix.
 These proteins serve as a channel for the selective transfer of polar molecules and
charged ions across the lipid barrier.
 Transmembrane proteins are found all over the membrane.

16. PASSAGE OF DRUGS ACROSS CELL MEMBRANES
• Passive Diffusion
• Filtration
• Specialized Transport:
• Active transport
• Facilitated diffusion

18. 1. Passive Diffusion
• Mechanism: Higher to Lower concentration
• Diffusion rate: Directly proportional to the concentration gradient
• Drug: Either a Weak Acid (Salicylates, Barbiturates etc.) or Weak Base (Morphine, Quinine etc.)
• Expressed by: Fick’s First Law of Diffusion
(Scott et al., 2017;Kramer et al., 2009).

20. 2 Facilitated Passive Diffusion
• Mechanism: Carrier-substrate Complex
• Energy-independent transport mechanism
• It is saturable
• E.g. Glucose, Amino Acid Transport, Gas Transport (O2)
(Friedman, 2008).

22. 3 Active Transport
• Against a concentration gradient
• Limited to the drug(s) which are similar in structure to the endogenous substances.
• Drug molecules engulfed by cell
• E.g. Iron salts, Levodopa, Propylthiouracil and Fluorouracil
• On the basis of ATP utilization, it can be classified into:
• Primary active transport
• Secondary active transport.
(Friedman, 2008);(Bottse et al., 1976)

24. Primary Active Transport ATP is required
• Only one ion or molecule can be transferred in one direction (uniporter) e.g.,
glucose absorption.
• Types:-
• P-type ATPase: Sodium-potassium Pump, Calcium Pump, Proton Pump
• F-ATPase: Mitochondrial ATP Synthase, Chloroplast ATP Synthase
• V-ATPase: Vacuolar ATPase
• ABC (ATP binding cassette) transporter: MDR*, CFTR**, etc.
* Multidrug Resistance
**Cystic Fibrosis Transmembrane Conductance Regulator
(Stillwell, 2016)

25. Secondary active transport Benefit of previously existing
concentration gradient (no direct ATP usage).
• Transport ions or molecules in the same direction (symport
or cotransport e.g. Na+/Glucose)
• In the opposite direction (antiport or counter-transport e.g.
Sodium - calcium antiporter or exchanger.)
(Stillwell, 2016)

26. Endocytosis
• Also a type of active transport process
• Transportation occurs within vesicles present inside the cell
• Transcellular process (transport of substance across the cell membrane)
• E.g. Macromolecular Drugs, Solid Particles, Oily Particles
• Classified into two categories (Levin et al., 2015):
• Pinocytosis (e.g. Absorption of nutrients in the GIT; )
• Phagocytosis (e.g. Intake of nutrients by egg cells (the human egg cells
before fertilization)
(Ghanghoria et al., 2016); (Ericson, 1981).