Presented By- Presented By- Anubhav Singh M.pharm 1st year IPR, GLA University.

INTRODUCTION

On its journey through the body, a drug needs to cross different biological barriers.

These barriers can be - A single layer of cells (e.g. the intestinal epithelium),

- Several layers of cells (e.g. in the skin), - Or the cell membrane itself (e.g. to reach an intracellular receptor).

A drug can cross a cell layer either by traveling through the cells (transcellular drug transport) or through gaps between the cells (paracellular drug transport).

Classification-

A. Transcellular drug transport

•In order to travel through a cell or to reach a target inside a cell, a drug molecule must be able to tranverse the cell membrane.

•Although cell membranes largely vary in their permeability characteristics depending on the tissue, the main mechanisms of drugs passing through the cell membrane are passive diffusion, carrier-mediated processes and vesicular transport.

•The 3 steps involved in transcellular transport of drugs are-

i.Permeation of GI epithelial cell membrane, a lipoidal barrier- this is the major obstacle to drug absorption.ii.Movement across the intracellular space (cytosol).iii.Permeation of the lateral or basolateral membrane- this is of secondary importance.

A.1. Passive Transport Process-

a. Passive diffusion

•Passive diffusion is the process by which molecules spontaneously diffuse from a region of higher concentration (e.g. outside of the cell) to a region of lower concentration (e.g. inside the cell), and it is the main mechanism for passage of drugs through membranes.

•Lipid-soluble drugs penetrate the lipid cell membrane with ease, and can pass the cell membrane by passive diffusion.

•Also, large molecules, such as proteins and protein-bound drugs, cannot diffuse through the cell membrane.

•The rate of diffusion depends, apart from the lipid/water partition coefficient of the drug (P) and the concentration gradient (C-out – C-in), on membrane properties such as the membrane area (A) and thickness (h), and the diffusion coefficient (D) of the drug in the membrane, according to Fick's law:

•Many drugs are acidic or basic compounds, which are ionized to a certain degree in aqueous medium. Their degree of ionization depends on their dissociation constant (pKa) and the pH of the solution, according to the Henderson-Hasselbach equation:

•Very weak acids with pKa values higher than 7.5, are essentially unionized at physiological pH values. For these drugs diffusion over the cell membrane is rapid and independent of pH changes within the body, provided the unionized form of the drug is lipid soluble.

•For acidic drugs with a pKa value between 3.0 and 7.5, the fraction of unionized drug varies with the changes in pH encountered in the organism. For these drugs the pH of the extracellular environment is critical in determining the diffusion across the cell membrane.

•For acidic drugs with a pKa lower than 2.5, the fraction of unionized drug is low at any physiological pH, resulting in very slow diffusion across membranes. A similar analysis can be made for bases.

b. Carrier-mediated processes

• Many cell membranes possess specialized transport mechanisms that regulate entry and exit of physiologically important molecules and drugs.

• Such transport systems involve a carrier molecule, that is, a trans membrane protein that binds one or more molecules and releases them on the other side of the membrane.

• Such systems may operate passively (without any energy source) and along a concentration gradient; this is called "facilitated diffusion."

• An example is the transport of vitamin B12 across the GI membrane.

• At high drug concentrations the carrier sites become saturated, and the rate of transport does not further increase with concentration. Furthermore, competitive inhibition of transport can occur if another substrate for this carrier is present.

Important characteristics of carrier-mediated transports are-

1. A carrier protein always has an uncharged (non-polar) outer surface which allows it to be soluble within the lipid of the membrane.

2. The should work efficiently in both direction.

3. Number of carriers are limited, the transport system is subject to competition between agents having similar structure.

4. Due to limited carriers at higher drug concentration the system becomes saturated.

5. Carrier-mediated absorption generally occurs from specific sites of the intestinal tract which are rich in number of carriers.

c. Ion-Pair Transport

• Mechanism that explains the absorption of drugs like quaternary ammonium compounds and sulphonic acids, which ionize under all pH conditions, is ion-pair transport.

• Despite their low o/w partition coefficient values, such agents penetrate the membrane by forming reversible neutral complexes with endogenous ions of the GIT like mucin.

• For example Propranolol, a basic drug that forms an ion pair with oleic acid, is absorbed by this mechanism.

d. Pore transport

• It is also known as Convective transport, bulk flow or filtration.

• This mechanism is responsible for transport of molecules into the cell through the protein channels present in the cell membrane.

• Characteristics-

i. The driving force is constituted by the hydrostatic pressure or the osmotic differences across the membrane due to which bulk flow of water along with small solid molecule occurs through such aqueous channels.

ii. The process is important in the absorption of low molecular weight (less than 100), low molecular size (smaller than the diameter of the pore).

iii. Chain like or linear compounds of molecular weight up to 400 daltons can be absorbed by filtration.

A.2 Active Transport

• In this process, there is direct ATP requirement.

• The process transfers only one ion or molecule and in only one direction, and hence called as uniporter. E.g. absorption of glucose.

a. Primary active transport

i. Ion Transporter- Responsible for transporting ions in or out of cells. e.g.- Proton pump, which is implicated in acidification of intracellular compartments.

•Two types of ion transporters which play important role in the intestinal absorption of drugs are-

a.Organic anion transporters: Absorption of drugs such as pravastatin and atorvastatin.

b.Organic cation transporters: Absorption of drugs such as diphenhydramine.

ii. ABC (ATP- binding cassette) transporters:

•Responsible for transporting small foreign molecules (like drugs and toxins) especially out of the cells i.e. Exsorption and thus called efflux pumps.

•Example of ABC transporter is P-glycoprotein. This later is responsible for pumping hydrophobic drugs especially anticancer drugs out of cells.

b. Secondary active transport

•In this process there is no direct requirement of ATP.

•The energy required in transporting an ion aids transport of another ion or molecule (co-transport or coupled transport) either in same direction or in opposite direction.

•This process further divided into-

i.Symport (co-transport)- Movement of both the molecules in same direction.

•E.g. Na+-glucose symporter uses the potential energy of the Na+ concentration gradient to move glucose against its concentration gradient.

•H+-coupled peptide transporter (PEPT1) which is implied in the intestinal absorption of peptide-like drug such as beta lactam antibiotics.

SYMPOTER- PEPT1

ii. Antiport (counter-transport)- Involves movement of molecules in the opposite direction.

•E.g. expulsion of H+ ions using the Na+ gradient in the kidneys.

•Drugs can also cross a cell layer through the small aqueous contact points (cell junctions) between cells. •This paracellular drug transport can be initiated by a concentration gradient over the cell layer (passive diffusion), or by a hydrostatic pressure gradient across the cell layer (filtration).

•For example, the endothelium of glomerular capillaries in the kidney forms a leaky barrier, which is very rich in intercellular pores. Therefore, this membrane is very permeable and permits filtration of water and solutes. On the other hand, endothelial cells of brain capillaries are sealed together by tight junctions, practically eliminating the possibility of paracellular drug transport.

B. Paracellular transport/Intercellular transport

There are two paracellular transport mechanisms involved in drug absorption-

i.Permeation through tight junctions of epithelial cells: Basically occurs through openings which are little bigger than the aqueous pores. Compounds such as insulin and cardiac glycosides are taken up by this mechanism.

ii.Persorption: Permeation of drug through temporary openings formed by shedding of two neighboring epithelial cells into the lumen.

C. Vesicular or Corpuscular Transport (Endocytosis)

• During vesicular transport the cell membrane forms a small cavity that gradually surrounds particles or macromolecules, thereby internalizing them into the cell in the form of a vesicle or vacuole.

• Vesicular transport is the proposed process for the absorption of orally administered Sabin polio vaccine and of various large proteins, It is called endocytosis when moving a macromolecule into a cell.

• Exocytosis when moving a macromolecule out of a cell.

• Transcytosis when moving a macromolecule across a cell.

Vesicular transport of dug can be classed into two categories-

i.Pinocytosis- cell drinking- uptake of fluid solute.ii.Phagocytosis- cell eating- adsorptive uptake of solid particulates.

Summary-

1. Brahmankar D.M.,”Biopharmaceutics and Pharmacokinetics- A Treatise”, 2nd Edition, 2009, published by Vallabh Prakashan, pp- 10 to 22.

2. Medicinal Chemistry 1, 2nd module, Pharmacokinetics and related topics.

3. Images from Google Images.

4. www.pharmainfo.net 

5. books.mcgraw-hill.com/medical/goodmanandgilman

6. pharmrev.aspetjournals.org

References-