Gastrointestinal Physiology and Drug Absorption

Oral Route Advantages

• Convenient and safe for patient self-administration
• Suitable for drugs that are poorly absorbed or unstable in other routes
• Allows for sustained-release mechanisms for prolonged action

GI Epithelial Mucus

• Role: Protects GI epithelium, lubrication for movement, creates a barrier to pathogens and irritants, and facilitates nutrient absorption
• Main components: Glycoproteins, proteins, lipids, and water
• Turnover time: Rapidly replaced to maintain integrity, varying in different regions of GI tract

Stomach

• Volumes: Fasting: ~25-50 mL; Fed: ~100-150 mL
• Roles: Food storage, initial digestion (protein breakdown), and mixing
• pH: ~1-3 (highly acidic)
• Secretions: HCl, pepsinogen, mucus
• MMC Phase III: Occurs in the fasted stomach

Small Intestine and Colon

• Small Intestine: ~6 meters long; High pH (6-7.5), primary site of drug absorption, influenced by factors like motility, surface area, and acidity
• Colon: ~1.5m long; Low pH (5.5-7.5), primary role of water/electrolyte absorption, limited drug absorption due to slower transit and less surface area

Gastric Motility

• Fasted Stomach: Primarily characterized by migrating motor complex (MMC)
• Fed Stomach: Characterized by mixing and peristaltic waves
• Factors affecting gastric residence time: Size of dosage form and size of meal
• Pyloric Sphincter: Controls the rate of gastric emptying into the small intestine

Gastric Residence Time

• Larger dosage/larger meal = increased gastric residence time
• Administration with water = faster intestinal transit than with food or on empty stomach

Drug Transit Time in Intestines

• Typical transit times: Small intestine (~1-3 hrs); Large intestine (~12-24 hrs)

Barriers to Drug Absorption

• Gut lumen: Food, enzymes, mucus
• Unstirred water layer: Thin layer of adhering fluid at the membrane surface
• Factors affecting absorption:
  • pH (gastric/intestinal); Food (including grapefruit juice); Disease states (e.g., inflammatory bowel disease)
  • Luminal enzymes (proteases, lipases, amylases) can affect drugs and drug formulations; excipients can be affected.

GI Membrane and Drug Transport

• Mechanisms: Passive diffusion, active transport, facilitated diffusion, or endocytosis
• Most common: Passive diffusion

Passive Diffusion

• Drugs most likely to use: Small, lipophilic molecules
• Factors affecting transport rate: Physicochemical properties of the drug, membrane nature, concentration gradient
• Sink conditions: Drug concentration in blood is substantially lower than in the GI fluids at the absorption sites
• Concentration gradient: Concentration higher in the gut lumen compared to the blood

Active Transport

• Mechanism: Mediated by carriers, requires energy input (ATP)
• Saturable: Transport rate is limited by carrier availability
• Molecules/drugs using this mechanism: Nutrients, some vitamins, some bile salts
• More than one mechanism? Drugs can use multiple mechanisms for absorption
• Relevant transporters: Short peptides, sugars, electrolytes

Facilitated Diffusion

• Energy requirement: No energy required;
• Transporters used for this mechanism
• Role in drug absorption: Plays a minor role in drug absorption

Endocytosis

• Mechanism: Cell membrane invaginates, forms vesicles encapsulating material
• Types: Pinocytosis, receptor-mediated endocytosis, phagocytosis
• Handling of drug macromolecules: Endocytosis, particularly phagocytosis, is used for absorption of large drug macromolecules

Paracellular Pathway

• Mechanism: Drug passage between adjacent cells in tight junctions
• Suitable drugs: Poorly lipid-soluble drugs with a small molecular weight

Drug Efflux

• Mechanism: Active transport out of enterocytes into the gut lumen
• Main protein: P-glycoprotein (P-gp) an ATP-binding cassette (ABC) transporter
• Effect on bioavailability: Decreases bioavailability of some drugs, especially those being actively effluxed.

Absorption Factors (Review Questions)

• Small intestine transit: Dependent on material type, fed/fasted state, and gastric emptying rate.
• Food presence: Can increase or decrease drug absorption
• Drug absorption: Can vary greatly with the presence or absence of food.

Noyes-Whitney Equation Factors

• Dissolution rate: Affected by diffusion coefficient (reduced by food), surface area (increased by smaller particle size), saturation solubility, thickness of the diffusion layer (influenced by motility), fluid volume.

Particle Size, Surface Area, and Dissolution

• Smaller particle size = greater surface area = faster dissolution rate
• Reduction of particle size does not always increase absorption for all drugs; dissolution rate is the limiting step in some cases.

Micronized Drug Use

• Micronization is not limited to oral preparations; beneficial for various dosage forms (ophthalmic, topical, pulmonary).

Weak Electrolytes

• Solubility: Weak acids - higher solubility in small intestine; Weak bases - higher solubility in stomach

Salt Forms

• Dissolution rate: Salt forms may increase the dissolution rate, generally the dissolution rate is faster for salts in aqueous solution than in the pure drug solution.
• Precipitation: Weak acids may precipitate in the stomach; fine precipitates dissolve faster.
• Dissolution location: Weak acids typically dissolve more in the intestine; Weak bases typically preferentially dissolve in the stomach.

Strongly Acidic Salts

• Rationale for using salt forms of drugs such as chlorpromazine hydrochloride is to enhance rapid dissolution in the more acidic stomach environment.

Bioavailability beyond Salt

• Factors considered: stability, hygroscopicity, manufacturability, crystallinity.
  • Examples: sodium salts for acidic drugs, hydrochloride salts for basic drugs.
• Poorly soluble salts may be used for extended-release formulations.

GI Fluid Concentration Factors

• Complexation: Can increase or decrease absorption
• Adsorption: Can interfere with drug absorption
• Chemical stability: Unstable drugs result in less drug being available for absorption

Drug Instability

• Common cause: Chemical instability (acid/enzyme hydrolysis)
• Strategies to increase stability: Lower dissolution rate: this can be achieved using salts, coatings
• Delaying dissolution: Enteric coatings, using salts of drugs that dissolve slowly in the stomach

Powder Form Drug Handling

• Solid form and properties (crystal properties) considered in powders for various dosage forms (tablets, suspensions, inhalers).

Solid State Forms

• Crystal forms: Crystalline, amorphous, semi-crystalline
• Common form: Crystalline

Amorphous Materials

• Formation: Fast solidification
• Penetration: Solvents penetrate easier through amorphous regions.
• Stability/Dissolution/Absorption: Amorphous usually more unstable and dissolves faster than crystalline; absorption usually better if dissolved faster.
• Amorphous to crystalline Transition: methods to increase amorphous form from a crystalline state.

Polymorphism

• Definition: Same chemical composition but different crystalline structures.
• Crystal form differences: Usually only present as a solid.
• Impacts: Dosage forms (tablets, capsules); solutions are not affected (generally)
• Metastable polymorphs: Can convert to stable polymorphs over time, or may be used for faster dissolution rates - stable polymorph is preferred for consistency.
• Bioavailability impact can be important depending on dissolution rate (limited absorption).

Hydrates and Solvates

• Definition: Hydrates trap water, solvates trap other solvents; pseudo-polymorphism, different solid forms exist based on solvent or water molecule trapping.
• Dissolution: Can be faster or slower than anhydrous forms based on how the water interacts with the crystal lattice.

pH-Partition Hypothesis

• Drug absorption: Primarily for lipid-soluble, non-ionized drugs.
• Weak electrolytes: Unionized forms more readily absorbed than ionized forms
• pH and ionization: Absorption extent depends on unionized form % at absorption site.

pH-Partition and Henderson-Hasselbalch Equation

• Acidic/basic drug absorption: Acids absorbed more in acidic environments (e.g., stomach); bases in basic environments (e.g., small intestine).

pH-Partition limitations

• Absorption affected by stability in GI environments, local pH differences between lumen & membrane, or binding of drug.

Lipid Solubility

• Importance: Crucial for passive diffusion across GI membrane.
• Estimation: Measuring partition coefficient: ratio of drug solubility in lipid vs. aqueous solvent

Explore the intricacies of drug absorption within the gastrointestinal tract, focusing on factors such as administration routes, mucus function, pH levels, and the unique characteristics of the small intestine. Understand how these elements influence drug dissolution, absorption rates, and overall bioavailability. Investigate the impact of food intake, dosage forms, and gastrointestinal pH on drug efficacy.