FACTORS INFLUENCING DRUG ABSORPTION THOUGH GIT

(A) PHARMACEUTICAL FACTORS

I. Physicochemical Properties of Drug Substances

1. Drug solubility and dissolution rate

2. Particle size and effective surface area
3. Polymorphism and amorphism
4. Pseudopolymorphism (hydrates/solvates)
5. Salt form of the drug
6. Lipophilicity of the drug
7. pKa of the drug and gastrointestinal pH → pH-partition hypothesis
8. Drug stability
9. Stereochemical nature of the drug

II. Dosage Form Characteristics and Pharmaceutical Ingredients (Pharmaco-

technical Factors)

1. Disintegration time (tablets/capsules)

2. Dissolution time
3. Manufacturing variables
4. Pharmaceutical ingredients (excipients/adjuvants)
5. Nature and type of dosage form
6. Product age and storage conditions

(B) PATIENT-RELATED FACTORS:

1. Age
2. Gastric emptying time
3. Intestinal transit time
4. Gastrointestinal pH
5. Disease states
6. Blood flow through the GIT
7. Gastrointestinal contents:
(a) Other drugs
(b) Food
(c) Fluids
(d) Other normal GI contents
8. Presystemic metabolism by:
(a) Luminal enzymes
(b) Gut wall enzymes
(c) Bacterial Enzymes
(d) Liver Metabolism (Hepatic First Pass)
 PHYSICOCHEMICAL PROPERTIES OF DRUG SUBSTANCES

1. Drug Solubility and Dissolution Rate

 A drug must dissolve in gastrointestinal (GI) fluids before it can be absorbed into the
bloodstream.
 Poor solubility = Poor absorption (e.g., hydrophobic drugs like Griseofulvin).
 Solubility: Maximum amount of drug that can dissolve in a given solvent (e.g., water)
at a specific temperature.
o Hydrophilic drugs (water-soluble) dissolve easily (e.g., glucose).
o Lipophilic drugs (fat-soluble) may need bile salts for solubilization (e.g., fat-soluble
vitamins).
 Dissolution Rate: Speed at which a drug dissolves.
o Noyes-Whitney Equation:
𝐷𝐴
Dissolution Rate = (𝐶𝑠 − 𝐶𝑏 )
ℎ
 D = Diffusion coefficient
 A = Surface area of drug
 h = Thickness of diffusion layer
 C_s = Saturation solubility
 C_b = Bulk concentration of drug in GI fluid

Example:

 Aspirin (weak acid) dissolves well in stomach acid (pH 1-3).

 Ketoconazole (weak base) dissolves better in intestinal pH (5-8).

2. Particle Size and Effective Surface Area

 Smaller particles = Larger surface area exposed to GI fluids → Faster dissolution →

Faster absorption.
 Micronization: Reducing particle size to 1–10 microns to enhance dissolution.

 Nanonization: Nanoparticles (<1 micron) further increase surface area (e.g.,

sirolimus nanoparticles).
Example:

 Griseofulvin (antifungal):
o Coarse particles: Poor absorption.
o Micronized form: 5x better absorption.

Exception:

 Too small particles may clump together (aggregation), reducing surface area.

3. Polymorphism and Amorphism

 Different polymorphs have different solubility, stability, and bioavailability.

 Polymorphs: Same chemical structure but different crystal packing.
o Stable polymorph: Low solubility, high stability (e.g., Ritonavir stable form
had poor bioavailability).
o Metastable polymorph: Higher solubility but may convert to stable form over
time.

 Amorphous form: No crystal structure → higher solubility but less stable (e.g.,
chloramphenicol palmitate).

Example:

 Carbamazepine:
o Form III (stable): Low solubility.
o Form I (metastable): Better absorption.

4. Pseudopolymorphism (Hydrates/Solvates)

 Anhydrous forms usually dissolve faster than hydrates/solvates.

 Hydrate: Drug + Water molecules (e.g., ampicillin trihydrate).
 Solvate: Drug + Organic solvent (e.g., ethanol solvate of theophylline).

Example:

 Theophylline:
o Anhydrous form: Faster dissolution.
 o Monohydrate form: Slower dissolution.

5. Salt Form of the Drug

 To improve solubility, stability, and absorption.

 Weak acids (e.g., aspirin) form salts with bases (e.g., sodium aspirin).
 Weak bases (e.g., atropine) form salts with acids (e.g., atropine sulfate).

Example:

 Sodium phenytoin (salt of phenytoin): More soluble than free acid form.

6. Lipophilicity of the Drug (log P)

 Drugs must be soluble enough in water to dissolve but lipophilic enough to cross cell
membranes.
 Optimal log P (~2–5): Good balance between solubility and permeability.
 Too high log P (>5): Poor dissolution (e.g., cyclosporine needs bile salts for
absorption).

Example:

 Propranolol (log P = 3.5): Well absorbed.

 Amiodarone (log P = 7.5): Poor oral bioavailability.

7. pKa and Gastrointestinal pH (pH-Partition Hypothesis)

 Determines whether a drug remains ionized (charged) or unionized (uncharged) in

different pH environments.

Key Concepts:

 Henderson-Hasselbalch Equation:
[A− ]
For acids: pH = pKa + log ( )
[HA]
[B]
For bases: pH = pKa + log ( )
[BH+ ]
  Unionized form crosses membranes easily.

Example:

 Aspirin (pKa = 3.5):

o In stomach (pH 1.5): Mostly unionized → Well absorbed.
o In intestine (pH 6.5): Mostly ionized → Poor absorption.

8. Drug Stability in GI Tract

 Some drugs degrade before absorption due to:

o Acid hydrolysis (e.g., penicillin G in stomach acid).
o Enzymatic degradation (e.g., insulin by peptidases).

Solutions:

 Enteric coating (protects from stomach acid).

 Prodrug approach (e.g., enalapril → enalaprilat).

9. Stereochemical Nature of the Drug

 Different enantiomers may have different absorption rates.

Example:

 Levodopa (L-Dopa): Well absorbed for Parkinson’s treatment.

 D-Dopa: Not absorbed effectively.
 DOSAGE FORM CHARACTERISTICS AND PHARMACEUTICAL INGREDIENTS

(PHARMACO-TECHNICAL FACTORS)

1. Disintegration Time (Tablets/Capsules)

 Disintegration is the breakdown of a solid dosage form (like tablets or capsules) into
smaller particles in the GI tract.
 Faster disintegration means the drug is released quicker, leading to faster
absorption.
 Example: A tablet that crumbles easily in the stomach will work faster than a hard,
slow-disintegrating one.

2. Dissolution Time
 Dissolution is the process where solid drug particles dissolve in GI fluids to become
absorbable.
 A drug must dissolve before it can be absorbed. Poor solubility = slower absorption.
 Example: A hydrophobic (water-repelling) drug dissolves slowly, delaying its effect.

3. Manufacturing Variables
 How a drug is made affects its absorption. This includes:
 Compression force (hard tablets dissolve slower).
 Coating type (enteric-coated tablets resist stomach acid).
 Granule size (smaller particles dissolve faster).
 Changes in production can alter drug release and absorption.

4. Pharmaceutical Ingredients (Excipients/Adjuvants)

 Excipients are inactive additives (e.g., binders, fillers, lubricants) in a drug.
 Some excipients help (e.g., disintegrants speed up breakdown), while others (like
certain lubricants) may slow absorption.
 Example: Magnesium stearate (a lubricant) can slow dissolution if used excessively.
5. Nature and Type of Dosage Form
 Different forms (tablets, capsules, liquids, suspensions) release drugs at different
rates.
 Liquids/syrups → Fastest absorption (already dissolved).
 Capsules → Faster than tablets (softer shell).
 Modified-release forms → Slow, controlled absorption.

6. Product Age and Storage Conditions

 Over time, drugs may degrade or change physically (e.g., tablets harden, coatings
crack).
 Old tablets may disintegrate/dissolve slower.
 Poor storage (heat/moisture) can ruin the drug’s structure.

 A damp-stored tablet may not work properly due to altered disintegration.

PATIENT-RELATED FACTORS

1. Age
 Infants & Elderly have differences in stomach acid levels, enzyme activity, and
intestinal motility.
 Infants: Stomach pH is less acidic (slows absorption of some drugs).
 Elderly: Slower gastric emptying & reduced blood flow → Delayed absorption.

2. Gastric Emptying Time

 The time taken for stomach contents to move into the small intestine (major site of
absorption).
 Faster emptying → Drug reaches intestines quickly → Faster absorption.
 Slower emptying (e.g., fatty meals, some diseases) → Delayed drug effect.
3. Intestinal Transit Time

 How long the drug stays in the intestines before excretion.

 Longer transit → More time for absorption (good for slow-absorbing drugs).
 Shorter transit (e.g., diarrhea) → Less absorption → Reduced drug effect.

4. Gastrointestinal pH
 Stomach (acidic pH) vs. Intestines (neutral to slightly basic pH).
 Acidic drugs (e.g., aspirin) absorb better in the stomach.
 Basic drugs (e.g., morphine) absorb better in the intestines.
 Changes in pH (e.g., antacids, infections) can alter drug absorption.

5. Disease States
 GI diseases (e.g., Crohn’s, celiac disease) → Damaged gut lining → Poor absorption.
 Achlorhydria (low stomach acid) → Affects breakdown of certain drugs.
 Liver disease → Altered metabolism → Changes drug availability.

6. Blood Flow Through the GIT

 More blood flow → Faster drug absorption (since absorbed drugs are quickly
carried away).
 Reduced blood flow (e.g., shock, heart failure) → Slower absorption.

7. Gastrointestinal Contents (What’s Already in the Stomach/Gut?)

(a) Other Drugs
 Drug interactions: Some drugs bind together (e.g., tetracycline + calcium → insoluble
complex → poor absorption).
(b) Food
 High-fat meals → Slow gastric emptying → Delayed absorption.
 Some drugs (e.g., griseofulvin) absorb better with fatty food.
 (c) Fluids
 Taking drugs with large amounts of water helps dissolve and absorb them faster.
(d) Other Normal GI Contents
 Bile salts help absorb fat-soluble drugs (e.g., vitamins A, D, E, K).

8. Presystemic Metabolism (First-Pass Effect)

Before a drug reaches systemic circulation, it can be partially destroyed by:
(a) Luminal Enzymes
 Digestive enzymes (e.g., pancreatic enzymes) may break down certain drugs.
(b) Gut Wall Enzymes
 Enzymes in the intestinal wall (e.g., CYP450 enzymes) metabolize drugs before they
enter the bloodstream.
(c) Bacterial Enzymes
 Gut bacteria can activate or deactivate certain drugs (e.g., sulfasalazine → activated
by colonic bacteria).
(d) Liver Metabolism (Hepatic First-Pass)
 Drugs absorbed from the gut pass through the liver, where enzymes (like CYP450)
may break them down before they reach circulation.
 ABSORPTION OF DRUG FROM NON PER-ORAL EXTRA-VASCULAR ROUTES

1. Buccal and Sublingual Routes

 Sublingual Route: This involves placing the drug under the tongue. This area has a
rich blood supply, allowing rapid absorption into the bloodstream. It is often used
for medications that require fast action, such as nitroglycerin for chest pain.

 Buccal Route: In this route, the drug is placed between the cheek and gum, where it
is absorbed through the oral mucosa into the bloodstream.
 Advantages of Both Routes:
1. Rapid Absorption: Both routes are highly vascularized, meaning drugs can
enter the bloodstream quickly.
2. No First-Pass Metabolism: Drugs bypass the liver's initial processing,
leading to higher drug concentrations in the bloodstream.
3. No Drug Degradation: Drugs are not exposed to stomach acid or digestive
enzymes, which can break down many drugs when taken orally.
 Key Factors:
1. Lipophilicity: Drugs need to be slightly fat-soluble (lipophilic) to pass
through the cell membranes in the oral mucosa efficiently.
2. Saliva: Saliva helps dissolve the drug and keep the oral mucosa moist, which
aids in drug absorption. Without sufficient saliva, absorption could be slower.
3. pH of Saliva: The pH of the saliva influences whether the drug stays in its
unionized (neutral) form, which is more likely to be absorbed.

2. Rectal Administration

 Use: The rectal route is used when other routes (oral or injections) are impractical
or not possible, especially in children, the elderly, or patients who are vomiting or
unconscious.
 Absorption: Drug absorption through the rectum is typically faster than through
the rectal suppositories because liquids are absorbed more rapidly.
 Factors that Slow Absorption:
1. Fecal Matter: The presence of fecal matter in the rectum can hinder absorption.
 2. Lower Surface Area: The rectum has a smaller surface area compared to other
parts of the gastrointestinal tract.

3. Topical Administration (Transdermal)

 Skin as a Route: The skin is an effective route for drugs that need to act locally (e.g.,
ointments for rashes) or systemically (e.g., nicotine patches). The skin serves as a
barrier, and drugs must pass through the epidermis to reach systemic circulation.
 Factors Affecting Absorption:
1. Stratum Corneum Thickness: The thicker the stratum corneum (outermost
skin layer), the slower the drug will be absorbed. For example, skin on the palms
and soles is thicker, so drug absorption is slower than in areas like the scalp
where there are hair follicles.
2. Hydration: Moist skin absorbs drugs better than dry skin. Applying emollients
or plastic film over the skin can enhance hydration and absorption.
3. Age: The skin changes with age, and older skin may absorb drugs differently due
to a reduction in blood flow and skin thickness.
4. Skin Surface Lipids: The skin’s surface is coated with lipids that can dissolve
drugs, making it easier for lipophilic drugs to pass through.

4. Iontophoresis

 What It Is: Iontophoresis is a technique where an electric current is used to drive

charged (ionic) drugs through the skin. The electric current repels charged drug
molecules, enhancing transdermal delivery.

 Application: This method is useful for delivering certain medications, such as

corticosteroids or local anesthetics, through the skin.
5. Intramuscular (IM) Administration

 Absorption Factors:
1. Blood Flow: The absorption rate from the muscle is dependent on the blood
flow to that muscle. For instance, the deltoid (upper arm) absorbs drugs faster
than the gluteal (buttock) region, where blood flow is slower.
2. Drug Lipid Solubility: Lipid-soluble drugs are absorbed more quickly through
passive diffusion in the muscle tissue.
3. Drug Size: Smaller molecules are more easily absorbed into the bloodstream
compared to larger molecules.

6. Subcutaneous (SC) Administration

 Slower Absorption: Drug absorption from the subcutaneous tissue is slower

compared to the intramuscular route. It is commonly used for medications that need
to be slowly absorbed, like insulin.

 Increasing Absorption: Methods to enhance absorption include improving blood

flow to the area (e.g., through massage or applying heat).

7. Pulmonary Administration

 Inhalation: Drugs are absorbed quickly via the lungs because of the large surface
area and rich blood supply in the alveoli. This route is used for medications like
bronchodilators (for asthma) or steroids for lung conditions.
 Particle Size: For effective lung absorption, drugs need to be in small particles (1-5
microns). Larger particles may not reach the lower respiratory tract, while too-small
particles may be exhaled before they can be absorbed.

8. Intranasal Administration

 Rapid Absorption: The nasal route is gaining popularity for delivering systemic
drugs, especially for peptide drugs. The nasal mucosa is highly vascularized, so
drugs can quickly enter the bloodstream.
  Factors Affecting Absorption:
1. Lipophilicity: Lipid-soluble drugs absorb faster through the nasal mucosa.
2. Molecular Size: Small molecules (under 1000 Daltons) are absorbed more
efficiently than larger ones.

9. Intraocular Administration:

 Eye as a Drug Delivery Site:

1. Drugs are applied topically to the eyes for local effects (e.g., glaucoma
treatment).

2. The cornea is the main barrier for drug penetration. The drug needs to have
both lipophilic and hydrophilic properties to pass through the cornea
effectively.

3. The pH of the tear fluid (lacrimal fluid) also influences drug absorption,
especially for weak electrolytes.

 Factors Affecting Absorption:

1. Formulation: Oily solutions, ointments, and gels are better for sustained
drug release since they stay longer on the eye surface.

2. Systemic Absorption: Sometimes, systemic absorption may occur,

especially with drugs like timolol used in glaucoma treatment. This can lead
to undesirable effects, so measures like pressing on the inner corner of the
eye (nasolacrimal occlusion) can be used to prevent it.

10. Vaginal Administration

 Used for Local and Systemic Treatment:

o Vaginal administration is used both for treating local infections (bacterial or

fungal) and for systemic drug delivery (e.g., contraception or hormone
therapy).
 o The vaginal route avoids first-pass metabolism (a benefit), and drugs can be
released in a controlled manner.

 Factors Affecting Vaginal Drug Absorption:

1. pH of Vaginal Fluids: The vaginal pH (4 to 5) plays a significant role in drug

absorption.

2. Microorganisms: The vaginal flora can impact how the drug is metabolized and
absorbed.