Oral Drug Absorption: GI Tract Factors

Oral Route Advantages

• Convenient and simple administration method
• Self-administered, reducing dependence on medical personnel
• Enables administration of various drug formulations

GI Epithelial Mucus

• Role: Protects the GI epithelium, facilitates nutrient absorption, and defends against pathogens
• Main Components: Glycoproteins, mucins, and electrolytes
• Turnover Time: Varies, depending on the location in the GI tract

Stomach

• Fed State Volume: Larger than fasting state
• Fasting State Volume: Smaller
• Roles: Digestion initiation, storage, and mixing of food
• pH: Highly acidic (1-3)
• Secretions: Gastric acid, pepsinogen, mucus, intrinsic factor
• MMC Phase III: Occurs during fasting, not the fed state

Small Intestine and Colon

• Small Intestine Length: Approximately 6-7 meters
• Small Intestine pH: Alkaline (6-8), essential for enzymatic digestion
• Small Intestine Role: Primary site of nutrient and drug absorption
• Colon Length: Approximately 1.5-2 meters
• Colon pH: Relatively acidic (6-7)
• Colon Role: Reabsorption of water and electrolytes
• Drug Absorption Factors: GI pH, motility, surface area, membrane properties

Gastric Motility and Residence Time

• Fasted Stomach: Mostly quiescent, with periodic migrating myoelectric complex ("housekeeping" waves)
• Fed Stomach: Increased motility, mixing, and propulsion of chyme
• factors affecting gastric residence time: Food volume and form, and gastric emptying rate.
• Pyloric Sphincter Role: Regulates the passage of chyme from the stomach to the small intestine, influencing drug transit time.

Gastric Drug Residence Time

• Meal size and volume affect gastric residence time.
• Drugs given with water are more likely to reach the intestine sooner than those taken with food.

Transit Times in Small and Large Intestines

• Variable transit time for drug in the small and large intestine

Barriers and Factors Affecting Drug Absorption

• Gut Lumen Barriers: Mucin, food particles, enzymes, and other absorption barriers.
• Unstirred Water Layer: A thin, stagnant layer of fluid at the surface of the GI membrane that slows down diffusion.
• GI pH Impact: Affects the ionization state of weak electrolytes, impacting absorption.
• Food Impact: Can alter dissolution rate, pH, and permeability, potentially impacting absorption.
• Grapefruit Juice Impact: May inhibit certain enzymes, affecting drug metabolism and absorption.
• Disease States Impact: May alter the GI environment, reducing or changing drug absorption.
• Luminal Enzymes: Enzymes like lipases can break down drug delivery systems and excipients.
• Types of Excipients digested by Lipases Lipid-based excipients.

GI Membrane and Drug Transport

• Drug Transport Mechanisms:
  • Passive diffusion
  • Active transport
  • Facilitated diffusion
  • Endocytosis (pinocytosis, receptor-mediated, phagocytosis)
  • Paracellular pathway
• Most Common Mechanism: Passive diffusion (for small lipophilic molecules)

Passive Diffusion

• Drugs that are small and lipophilic are most likely to be absorbed via passive diffusion.
• Factors affecting passive diffusion rate: physicochemical properties of the drug, characteristics of the GI membrane, and concentration gradient.
• "Sink conditions" are maintained when the drug concentration in the blood is much lower than in the GI fluids.

Active Transport

• ATP-dependent
• Carrier-mediated
• Saturable
• Used for nutrients, some vitamins, and bile salts.
• Can transport drugs against concentration gradients.
• Specific chemical structures are needed.
• Drugs can use multiple transport mechanisms.

Facilitated Diffusion

• Not energy-dependent
• Carrier-mediated
• Saturable
• Plays a minor role in drug absorption.

Endocytosis

• Types: Pinocytosis, receptor-mediated endocytosis, and phagocytosis.
• Used for larger macromolecules like oral Sabin polio vaccine.

Paracellular Pathway

• Movement of drugs between intestinal epithelial cells.
• Used typically for poorly lipid-soluble drugs; small molecular weight drugs.

Drug Efflux

• P-glycoprotein (P-gp) is a major efflux protein in the small intestine.
• P-gp can reduce drug bioavailability if the drug is a substrate.
• Can be affected by inhibitors like verapamil or quinidine.

Review Questions

• Small intestine drug transit is dependent on the material type and gastric emptying rate
• Food can increase or decrease drug absorption.

Noyes-Whitney Equation

• Factors Affecting Dissolution Rate: Food, surfactants, agitation, volume
• Diffusion Coefficient in GI Fluids: Decreased by food (due to increased viscosity)
• Motility Impact: Increased motility enhances dissolution (by lowering diffusion layer thickness)
• Fluid Volume: Larger volume generally yields a higher dissolution rate.

Particle Size, Surface Area, and Dissolution

• Smaller particle size increases surface area, leading to increased dissolution rate.
• Dissolution rate, not all drug absorption, is enhanced with reduced particle size.
• When dissolution is the rate-limiting step (i.e., dissolution-rate limited absorption), smaller size yields better absorption.

Micronized Drugs

• Micronization can benefit various dosage forms (not just oral)

Weak Electrolytes

• Weak acids solubility is higher in the intestine
• Administration of a cimetidine will decrease absorption of a weak base drug.

Drug Salt Forms – Dissolution

• Salts can increase dissolution rate by altering pH or creating fine precipitates.
• Weak acid salts often precipitate in a fine form, dissolving faster in the intestine.
• Weak acids dissolve mostly in the intestine.
• Salt forms (e.g., sodium or hydrochloride salt) are more suitable for treatments like toothaches.

Strongly Acidic Salts

• Using a strong acid to form a salt for a weak base drug often increases dissolution.
• Acidic salts reduce pH of diffusion layer, promoting dissolution.

Beyond Bioavailability Salt Selection

• Stability, hygroscopicity, manufacturability, and crystallinity factors are considered beyond bioavailability.
• Examples of common drug salts: Sodium salts and hydrochloride salts.

Factors Affecting Drug Concentration

• Complexation: May increase or decrease absorption depending on the drug and complex.
• Adsorption: Concurrent use of adsorbents can decrease drug absorption.
• Chemical Stability: Instability in fluids reduces drug absorbed.
• Micellar Solubilization: May improve drug solubility.

Drug Complexation

• Complexation can either increase or decrease drug absorption.
• Excipients can form complexes with drugs.
• Cyclodextrin complexation is often reversible.
• Complexation can increase bioavailability, particularly for certain drugs.

Drug Instability in GI Tract

• Chemical instability (hydrolysis) is a frequent problem.
• To enhance stomach stability, decrease dissolution rate.
• GI stability methods include enteric coating or use of different salts.

Drug Handling in Powder Form

• Almost all drug manufacturing employs powder at some stages.
• Solids crystal properties must be considered to ensure final dosage forms properties meet specifications.

Solid State Forms

• Solids can be crystalline, amorphous, or semi-crystalline
• Crystalline forms are most common in drugs and excipients

Amorphous Materials

• Created by rapid solidification
• Methods to increase the amorphous content of a substance already in crystal form include milling.
• Amorphous forms dissolve faster and often absorb better in situations where the dissolution rate limits drug absorption.

Polymorphism and Polymorphs

• Polymorphism: Substances capable of existing in multiple crystal forms.
• No chemical differences inherent within polymorphs.
• Polymorphism only affects the solid state.
• Polymorphism affects various dosage forms (tablets, capsules, suspensions).
• Polymorphic transitions can occur during processing.

Metastable Polymorphs

• Metastable polymorphs can convert to stable polymorphs over time (spontaneously).
• A material can only have one stable form.
• For things like suppositories, keeping the stable polymorph is desired. Avoiding melting into a less suitable form.

Polymorph Properties

• Metastable forms often dissolve and absorb better than the stable polymorph, but this difference isn't always significant.
• Differences between stable and metastable polymorphs are critical for slow-dissolution drugs.

Hydrates, Solvates, and Pseudo-polymorphism

• Hydrates: crystals that trap water.
• Solvates: crystals that trap other solvents.
• Pseudo-polymorphism: In essence, drug compounds can have a broader classification (beyond polymorph structure) in the solid state.
• Anhydrous forms can have faster or slower dissolution rates depending on mechanism.

pH-Partition Hypothesis

• Drugs more lipid soluble have greater absorption (unionized forms).
• Most drugs are weak electrolytes, the more unionized a weak electrolyte the more lipid soluble it is expected to be.
• Unionized form penetrates the GI membrane more effectively via passive diffusion.
• Drug absorption depends primarily on the unionized form at absorption site.

pH-Partition and Henderson-Hasselbalch

• Weak acids absorb better in acidic environments (stomach)
• Weak bases absorb better in basic environments (intestine)
• pH-partition hypothesis has limitations and is not the sole determinant of absorption.

Lipid Solubility and Partition Coefficient

• Lipid solubility is crucial for absorption.
• Partition coefficient measures relative solubility in lipid versus water.
• Low lipid solubility drugs may use different mechanisms (like paracellular transport).
• Higher logP (lipid solubility) correlates frequently with higher absorption (homologous series).

Explore factors influencing oral drug absorption, including GI mucus, stomach pH, and the small intestine. Mucus protects the epithelium, while the stomach initiates digestion with its acidic environment. The small intestine's alkaline pH is essential for drug absorption.