Mechanism of drug absorption

Passive diffusion Carrier mediated transport Pore transport Ionic or electrochemical diffusion Ion pair transport Endocytosis Active transport

PASSIVE DIFFUSION

FICK’S 1ST LAW OF DIFFUSIONdQ/dt = DAKm/w (CGIT-C)

h

The parameters of this equation are:- D: diffusion coefficient - related to the size and lipid solubility of the

drug, the viscosity of the diffusion medium, the membrane. A: surface area. As the surface area increases the rate of diffusion also

increases. Absorption is generally faster from the intestine compared with absorption from the stomach.

h: membrane thickness. The smaller the membrane thickness the quicker the diffusion process. As one example, the membrane in the lung is quite thin thus inhalation absorption can be quite rapid.

(Cgit -C): concentration difference.

CARRIER MEDIATED TRANSPORT

CARRIER MEDIATED TRANSPORT Structure specific Competition between similar structures Can be explained by Michaelis –Menten

equation Cefazolin…

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Active Transport Active transport

requires a carrier molecule and a form of energy. Eg aa, glucose

the process can be saturated

transport can proceed against a concentration gradient

competitive inhibition is possible

Active transportCharacteristics Uphill transport Energy is utilized Inhibited by metabolic poisons like fluorides,

cyanides and dinitrophenol and lack of oxygen.

E.g. Na+,K+.Ca2+,iron, glucose, Amino acids and vitamins like niacin, pyridoxine and ascorbic acid.

Active transport Drugs having structure similar to such

agents are absorbed. E.g. absorption of 5-flurouracil and 5-

bromouracil via pyrimidine transport system. Absorption of methyldopa and levodopa via

the L-amino acid transport system. Absorption of ACE inhibitor enalapril via

small peptide carrier system. Active transport is also important in renal

and biliary excretion of many drugs and their metabolites.

Facilitated diffusion

Facilitated diffusion A drug carrier is required but no energy is

necessary. Characteristic Downhill transport No energy required Not inhibited by metabolic poisonE.g. Entry of glucose in RBC Intestinal absorption of vit B1 and B2 Glycoprotein + vitamin B12 = complex –carrier

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Carrier mediated Transport

Pore (Convective) Transport Very small molecules (such as urea, water, and

sugars) are able to cross cell membranes rapidly, as if the membrane contained channels or pores.

The model of drug permeation through aqueous pores is used to explain renal excretion of drugs and the uptake of drugs into the liver.

A certain type of protein called a transport protein may form an open channel across the lipid membrane of the cell.

Small molecules including drugs move through the channel by diffusion more rapidly than at other parts of the membrane.

PORE TRANSPORT

Ionic diffusion Strong electrolyte drugs maintain their charge at all

physiologic pH values and penetrate membranes poorly. When the ionized drug is linked up with an oppositely

charged ion, an ion pair is formed in which the overall charge of the pair is neutral.

This neutral drug complex diffuses more easily across the membrane. For example, the formation of ion pairs to facilitate drug absorption has been demonstrated for propranolol, a basic drug that forms an ion pair with oleic acid, and quinine, which forms ion pair with hexylsalicylate .

An interesting application of ion pairs is the complexation of amphotericin B and DSPG (disteroylphosphatidylglycerol) in some amphotericin B/liposome products.

Ion pairing may transiently alter distribution, reduce high plasma free drug concentration, and reduce renal toxicity.

Vesicular Transport Vesicular transport is the process of

engulfing particles or dissolved materials by the cell.

Two type 1. Exocytosis 2. Endocytosis. Endocytosis and exocytosis are the

processes of moving specific macromolecules into and out of a cell, respectively.

Vesicular Transport

Endocytosis Pinocytosis (cell drinking) refers to the

engulfment of small solutes or fluid. E.g. Orally administered Sabin Polio Vaccine

and large protein molecules. whereas phagocytosis (cell eating) refers to

the engulfment of larger particles or macromolecules, generally by macrophages.

Cellular uptake of macromolecular nutrients like fats and starch, oil soluble vitamins like A,D,E and K and drugs such as insulin.

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Examples of MembranesBlood/ Brain Lipid membrane For lipohilic drugs onlyBlood kidney (Bowman’s )

Lipid membrane with large pores

For both lipophilic and hydrophilic drugs

Blood/Kidney (Tubuli)

Lipid membrane For lipophilic drugs only

Lung Lipid membrane with pores

For both lipohilic and hydrophilic drugs

Stomach Lipid membrane with few pores

For lipophilic, non ionised acidic drugs

Small intestine Lipid membrane with few pores

For lipophilic drugs (acidic & Basic), less for hydrophilic drugs

In vitro absorption models1. Diffusion cells2. Segments of GIT laboratory animals Everted sac technique Everted ring technique3. Cell cultures of gut epithelium Eg: Caco-2-cells

polycarbonate membrane treated with collagen

In situ absorption models1. Doluisio method

1. Radio labeled drug with non absorble marker

2. Single pass perfusion

Cannulated Conscious Rat Models