MECHANISM OF DRUG ABSORPTION MECHANISM OF DRUG ABSORPTION

MECHANISM OF DRUG ABSORPTION

MECHANISM OF DRUG ABSORPTION Contents • Introduction of drug absorption. • Mechanism of Drug absorption a) Transcellular 1. Passive transport process a) Passive diffusion b) Pore transport c) Ion-pair transport d) Facilitated diffusions 2. Active transport process a) Primary active transport. b) Secondary active transport. b) Paracellular c) Vesicular 1. Pinocytosis 2. Phagocytosis • Reference

Introduction of drug absorption. • The process of movement of unchanged drug from the site of administration to systemic circulation. • There always exist a correlation between the plasma concentration of a drug & therapeutic response & thus, absorption can also be defined as the process of movement of unchanged drug from the site of administration to the site of measurement. i. e. , plasma.

Mechanism Of Drug Absorption The three broad categories of drug transport mechanisms involved in the absorption are: 1. Transcellular / intracellular transport 2. Paracellular/ intercellular transport 3. Vesicular transport

Transcellular / intracellular transport • It is defined as the passage of drugs across the GI epithelium. • The three steps involved in transcellular transport of drug are: 1. Permeation of GI epithelial cell membrane 2. Moment across the intracellular space (cytosol). 3. Permeation of the lateral or basolateral membrane.

• The various transcellular transport processes involved in the drug absorption are. 1. passive transport process. 2. active transport process. 1. Passive transport process: can be further classified into following types. a) passive diffusion b) pore transport c) Ion-pair transport d) Facilitated or mediated diffusion

2. Active transport process. It is are of 2 types, as shown below a) Primary active transport b) Secondary active transport – symport – Antiport.

2. Paracellular/ intercellular transport • It is defined as the transport of drugs through the junctions between the GI epithelial cells. • The two paracellular transport mechanism involved in the drug transport as shown below. 1. Permeation through tight junctions of epithelial cells 2. Persortion

3. Vesicular transport or Endocytosis. • These are also energy dependent processes but involves transport of substances within vesicles into a cell. Since the mechanism involves transport across the cell membrane, it can be classified into two categories. a) Pinocytosis b) Phagocytosis.

Compares the transcellular, paracellular and vesicular transport mechanism

Passive diffusion • Also called as non ionic diffusion, • it is the major process for the absorption of more than 90% of the drugs. • It is defined as the difference in the drug concentration on either side of the membrane. • The driving force for this process is the concentration or electrochemical gradient.

Fick’s 1 st Law Of Diffusion d. Q/ dt = DAKm/w (C git-C) h d. Q/ dt- rate of drug diffusion ( amount/ time). D – diffusion coefficient of the drug through the membrane. A- surface area of the absorbing membrane for drug diffusion. Km/w- partition coefficient of the drug b/w the lipoidal membrane and aqs GIT. (C git-C)- difference in concentration of the drug in the GI fluid and the plasma h – thickness of the membrane

• a) b) c) d) • • Certain characteristic of passive diffusion can be generalized. Down hill transport Greater the surface area & lesser the thickness of the membrane, faster the diffusion. Equilibrium is attained when the concentration on either side of the membrane become equal. Greater the membrane/ water partition coefficient of drug, faster the absorption. Passive diffusion process is energy independent but depends more or less on the square root of the molecular size of the drugs. The mol. Wt. of the most drugs lie between 100 to 400 Daltons which can be effectively absorbed passively.

Relative Permeability Of Different Molecules To Lipid Bilayer.

Pore transport. • It is also called 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. • Important in the absorption of low mol. wt. , low mol. size & generally water-soluble drugs e. g. urea, water &sugars.

Pore transport. • The driving force for the passage of the drugs is the hydrostatic or the osmotic pressure

Pore transport. • The rate of absorption via pore transport depends on the number & size of the pores, & given as follows: dc dt where, dc = dt N = R = ∆C = η = = N. R 2. A. ∆C (η) (h) rate of the absorption. number of pores radius of pores concentration gradient viscosity of fluid in the pores

Ion pair transport. It is another mechanism is able to explain the absorption of such drugs which ionize at all p. H condition. • Transport of charged molecules due to the formation of a neutral complex with another charged molecule carrying an opposite charge. • Drugs have low o/w partition coefficient values, yet these penetrate the membrane by forming reversible neutral complexes with endogenous ions. e. g. mucin of GIT. •

Ion pair transport. • Such neutral complexes have both the required lipophilicity as well as aqueous solubility for passive diffusion. E. g. propranol

Ion pair transport.

Carrier- mediated transport. • Involves a carrier which binds reversibly with the solute molecules to be transported to yield the carrier solute complex which transverses across the membrane to the other side where it dissociates to yield the solute molecule • The carrier then returns to its original site to accept a fresh molecule of solute. • There are two types of carrier mediated transport system: a) facilitated diffusion b) active transport

Carrier- mediated transport • .

Carrier- mediated transport

a) Facilitated Diffusion • This mechanism involves the driving force is concentration gradient. • In this system, no expenditure of energy is involved (down-hill transport), therefore the process is not inhibited by metabolic poisons that interfere with energy production. • A classical example of passive facilitated diffusion is the gastro-intestinal absorption of vitamin B 12. • An intrinsic factor (IF), a glycoprotein produced by the gastric parietal cells, forms a complex with vitamin B 12 which is then transported across the intestinal membrane by a carrier system

a) Facilitated Diffusion

b) Active Transport • More important process than facilitated diffusion. • The driving force is against the concentration gradient or uphill transport. • Since the process is uphill, energy is required in the work done by the barrier. • As the process requires expenditure of energy, it can be inhibited by metabolic poisons that interfere with energy production. • It is classified as primary and secondary active transport

Active Transport

• The rate of absorption by active transport can be determined by applying the equation used for Michalies-menten kinetics: dc = [C]. (dc/dt)max dt Km + [C] Where, (dc/dt)max = maximal rate of drug absorption at high drug concentration. [C] = concentration of drug available for absorption Km = affinity constant of drug for the barrier.

Comparison of active and passive transport mechanism

Endocytosis. • It involves engulfing extracellular materials within a segment of the cell membrane to form a saccule or a vesicle (hence also called as corpuscular or vesicular transport) which is then pinched off intracellular. • Sometimes, an endocytotic vesicle is transferred from one compartment to another. Such phenomenon is called transcytosis.

Endocytosis. • Endocytosis includes two types of processes 1. Phagocytosis 2. Pinocytosis Phagocytosis • This process involves the absorptive uptake of solid particulates, macromolecules. • It is also called as cell eating. Pinocytosis • This process is important in the absorption of oil soluble vitamins & in the uptake of nutrients.

Endocytosis.

Comparison

Reference Jaiswal, • D. M. Brahmankar & Sunil B. Biopharmaceutics & pharmacokinetics 2 nd ed. , vallabh prakashan pg no. 5 -23 • www. google. com

Thank U