Drug Absorption

Absorption

Drug absorption is the process by which a drug moves from its site of administration into the systemic circulation. It is a crucial step in pharmacokinetics, as only the absorbed fraction of a drug is capable of producing a pharmacological effect. The rate and extent of absorption influence the onset, intensity, and duration of drug action. For orally administered drugs, absorption mainly occurs in the gastrointestinal tract, particularly in the small intestine, due to its large surface area and rich blood supply.

A. factor affecting drug absorption

1. Drug solubility & dissolution rate
2. Particle size & effective surface area
3. Polymorphism & amorphism
4. Pseudo polymorphism
5. Salt form of the drug
6. pKa of drug & gastrointestinal pH
7. Drug stability

B. Pharmaceutical factors

1. Disintegration time
2. Dissolution time
3. Manufacturing variables
4. Pharmaceutical ingredients
5. Nature & type of dosage form
6. Product age & storage condition

C. Patient-related factor

1. Route of administration

2. Membrane physiology

a) Nature of the cell membrane 

b) Transport processes

3. Age

4. Gastric emptying time

5. Intestinal transit time

6. Gastrointestinal pH

7. Disease states

8. Gastrointestinal contents:

a) Food-drug interaction

b) Fluids

c) Other normal GI contents

9. Blood flow through the GIT

10. Pre-systemic metabolism by:

a) Luminal enzymes

b) Gut wall enzymes

c) Hepatic enzymes

d) Bacterial enzymes

Factors Affecting Drug Absorption

Drug absorption is influenced by multiple factors, which can be classified into drug-related factors, pharmaceutical factors, and patient-related factors.

A. Drug-Related Factors Affecting Drug Absorption

The physicochemical properties of a drug play a major role in determining its rate and extent of absorption. These factors influence how readily a drug dissolves, permeates biological membranes, and remains stable in the gastrointestinal environment.

1. Drug Solubility and Dissolution Rate

For a drug to be absorbed, it must first dissolve in the biological fluids at the site of administration. Poorly soluble drugs exhibit slow and incomplete absorption, whereas highly soluble drugs are absorbed more rapidly. The dissolution rate refers to the speed at which a solid drug dissolves in gastrointestinal fluids. According to the Noyes–Whitney equation, a faster dissolution rate leads to improved absorption. Drugs with low aqueous solubility often show reduced bioavailability, especially when administered orally.

2. Particle Size and Effective Surface Area

Particle size significantly influences drug absorption. Reduction in particle size increases the effective surface area available for dissolution. As surface area increases, the dissolution rate also increases, leading to faster and more complete absorption. Micronized and nonionized drug particles are commonly used to enhance the absorption of poorly soluble drugs.

3. Polymorphism and Amorphism

Polymorphism refers to the ability of a drug to exist in more than one crystalline form. Different polymorphic forms of the same drug may show variations in melting point, solubility, dissolution rate, and stability. Generally, metastable polymorphs dissolve faster than stable forms, resulting in better absorption.

Amorphous forms lack a definite crystalline structure and usually exhibit higher solubility and dissolution rates compared to crystalline forms, leading to enhanced absorption.

4. Pseudo-Polymorphism

Pseudo-polymorphism occurs when drug molecules incorporate solvent or water molecules into their crystal lattice, forming hydrates or solvates. These forms may show altered physicochemical properties such as solubility, stability, and dissolution rate. Hydrated forms are often less soluble than anhydrous forms, which may reduce drug absorption.

5. Salt Form of the Drug

Conversion of a drug into its salt form is a common strategy to improve solubility and dissolution rate. Salt forms of weak acids and weak bases generally dissolve more readily in gastrointestinal fluids than their free base or free acid forms. Improved solubility enhances the rate and extent of absorption. However, the choice of salt form must consider drug stability and compatibility.

6. pKa of Drug and Gastrointestinal pH

The degree of ionization of a drug depends on its pKa and the pH of the gastrointestinal tract. According to the pH-partition hypothesis, drugs are absorbed more efficiently in their non-ionized form, as it is more lipid-soluble and can easily cross biological membranes. Weak acids are better absorbed in acidic environments, whereas weak bases are better absorbed in alkaline conditions. Variations in GI pH can therefore significantly affect drug absorption.

7. Drug Stability

Drug stability in the gastrointestinal tract is essential for effective absorption. Some drugs may undergo degradation due to acidic gastric pH, digestive enzymes, or intestinal microflora before being absorbed. Unstable drugs show reduced bioavailability. Protective formulations such as enteric coating or prodrug design are often used to improve stability and enhance absorption.

B. Pharmaceutical Factors Affecting Drug Absorption

Pharmaceutical factors are related to the formulation and processing of a drug product. These factors influence the release of the drug from the dosage form and its subsequent availability for absorption at the site of administration.

1. Disintegration Time

Disintegration time is the period required for a solid dosage form, such as a tablet or capsule, to break down into smaller particles after administration. For orally administered solid dosage forms, disintegration is an essential step before dissolution and absorption can occur. A shorter disintegration time generally leads to faster drug release and quicker onset of action, whereas delayed disintegration may reduce the rate of absorption.

2. Dissolution Time

Dissolution time refers to the time taken for the drug to dissolve in the gastrointestinal fluids after disintegration. Since only dissolved drug molecules can be absorbed, dissolution is considered a critical step in drug absorption. Drugs with faster dissolution rates show improved bioavailability, while slow dissolution may lead to incomplete or delayed absorption.

3. Manufacturing Variables

Manufacturing processes significantly affect drug absorption. Factors such as compression force, granulation method, particle size distribution, and coating techniques influence tablet hardness, porosity, and drug release characteristics. Excessive compression may slow disintegration and dissolution, while improper coating can delay or reduce drug release.

4. Pharmaceutical Ingredients (Excipients)

Excipients are inactive substances added to a formulation to aid in manufacturing and drug delivery. They can influence absorption by affecting disintegration, dissolution, and stability. For example, disintegrants promote tablet breakup, while binders and lubricants may slow drug release. Some excipients enhance drug solubility and permeability, thereby improving absorption.

5. Nature and Type of Dosage Form

The type of dosage form plays a major role in determining the rate and extent of drug absorption. Liquid dosage forms are generally absorbed faster than solid forms because the drug is already in solution. Modified-release dosage forms are designed to control the release rate of the drug, thereby altering absorption patterns to achieve prolonged therapeutic effects.

6. Product Age and Storage Conditions

The age of the pharmaceutical product and its storage conditions can affect drug stability and performance. Exposure to heat, moisture, light, or improper storage may cause degradation of the drug or changes in the dosage form, leading to altered disintegration, dissolution, and absorption. Proper packaging and storage are essential to maintain drug quality and bioavailability.

C. Patient-Related Factors Affecting Drug Absorption

Patient-related factors are physiological and pathological conditions of the individual that influence the rate and extent of drug absorption. These factors vary among individuals and can significantly alter drug bioavailability.

1. Route of Administration

The route by which a drug is administered greatly influences its absorption. Oral, parenteral, topical, inhalational, and transdermal routes differ in absorption rate and extent. For example, intravenous administration bypasses absorption, whereas oral administration requires passage through the gastrointestinal tract, where several variables can affect absorption.

2. Membrane Physiology

Drug absorption largely depends on the ability of drug molecules to cross biological membranes.

Nature of Cell Membrane

Biological membranes are composed mainly of lipid bilayers with embedded proteins. Lipid-soluble drugs cross membranes more easily than water-soluble drugs.

Transport Processes

Drug transport across membranes may occur via passive diffusion, active transport, facilitated diffusion, or endocytosis. The efficiency of these processes affects absorption.

3. Age

Age-related physiological differences influence drug absorption. In infants, immature gastric acid secretion and enzyme activity may alter absorption. In elderly individuals, reduced gastric motility, blood flow, and enzyme activity can affect the rate and extent of absorption.

4. Gastric Emptying Time

Gastric emptying time determines how quickly a drug reaches the small intestine, the major site of absorption. Faster gastric emptying usually enhances absorption, while delayed emptying slows drug absorption.

5. Intestinal Transit Time

Intestinal transit time refers to the duration the drug remains in the intestine. Adequate contact time with the absorptive surface is necessary for optimal absorption. Very rapid transit may reduce absorption.

6. Gastrointestinal pH

The pH of the gastrointestinal tract influences drug ionization and solubility. Weak acids are better absorbed in acidic environments, while weak bases are better absorbed in alkaline conditions. Changes in GI pH can significantly affect drug absorption.

7. Disease States

Certain diseases, such as diarrhea, malabsorption syndromes, liver disease, and gastrointestinal disorders, can alter drug absorption by affecting GI motility, pH, enzyme activity, or blood flow.

8. Gastrointestinal Contents

The presence of food and other contents in the GI tract can influence drug absorption.

Food–Drug Interaction

Food may delay gastric emptying, alter pH, or bind with drugs, thereby increasing or decreasing absorption.

Fluids

Adequate fluid intake can help dissolve drugs and improve absorption.

Other Normal GI Contents

Bile salts, mucus, and digestive secretions may interact with drugs and affect absorption.

9. Blood Flow Through the Gastrointestinal Tract

Increased blood flow maintains a concentration gradient across the intestinal membrane, thereby enhancing drug absorption. Reduced blood flow, as seen in shock or heart failure, may decrease absorption.

10. Pre-Systemic Metabolism (First-Pass Effect)

Some drugs undergo metabolism before reaching systemic circulation, reducing their bioavailability. This occurs due to:

Luminal Enzymes

Enzymes present in the GI lumen may degrade drugs.

Gut Wall Enzymes

Drugs may be metabolized by enzymes present in the intestinal wall.

Hepatic Enzymes

After absorption, drugs pass through the liver, where extensive metabolism may occur.

Bacterial Enzymes

Gut microflora can metabolize certain drugs, altering their absorption and activity.

Bioavailability

Bioavailability is the rate and extent to which an active drug ingredient is absorbed from a pharmaceutical dosage form and becomes available at the site of action or in systemic circulation.

Factors affecting bioavailability:

• First-pass metabolism (liver and gut wall)
• Drug solubility and dissolution rate
• Dosage form and formulation
• Route of administration
• Gastrointestinal pH and motility
• Food–drug interactions