Factors Influencing Drug Absorption
Factors Influencing Drug Absorption: Drug absorption is defined as the process through which a drug molecule travels from the site of administration into the systemic circulation. In the case of orally administered pharmaceuticals, absorption occurs primarily across the epithelial lining of the gastrointestinal tract (GIT). The efficiency, rate, and extent of absorption significantly determine the bioavailability of the drug, ultimately influencing its pharmacological efficacy and clinical outcome.
The human GIT is a dynamic, complex, and highly specialized system. It presents both opportunities and challenges for drug delivery due to its variable pH, enzymatic activity, mucosal architecture, transit times, and microbial flora. Therefore, understanding the multifaceted factors that govern drug absorption is crucial for pharmaceutical formulation scientists, clinical pharmacologists, and healthcare professionals alike.
This extensive overview delves into the major determinants of oral drug absorption, including physicochemical characteristics of the drug, physiological and anatomical variables of the GIT, formulation considerations, and interactive influences such as food and co-administered medications.
1. Physicochemical Properties of the Drug
a. Aqueous Solubility
Solubility is one of the most critical physicochemical attributes that determine the fraction of drug available for absorption. A drug must first dissolve in the aqueous milieu of the gastrointestinal fluids before it can permeate through the mucosal membrane.
- Hydrophilic drugs may dissolve easily but might face barriers in permeating lipid membranes.
- Lipophilic drugs may permeate membranes easily but suffer from poor aqueous solubility.
Formulation Approaches: Solubility enhancement strategies include salt formation, co-solvency, use of surfactants, solid dispersions, and complexation with cyclodextrins.
b. Particle Size and Surface Area
Smaller drug particles possess a greater surface area relative to their volume, facilitating a faster dissolution rate according to the Noyes–Whitney equation.
- Micronization and nanonization are modern techniques used to reduce particle size and enhance the dissolution rate.
- Enhanced dissolution leads to increased concentrations in the GI lumen, improving the rate and extent of absorption.
Example: Micronized fenofibrate has higher bioavailability compared to the standard form.
c. Degree of Ionization and pKa
The extent of ionization affects both solubility and permeability. The Henderson-Hasselbalch equation describes the relationship between the drug’s pKa and the pH of the environment, determining the ionized-to-unionized ratio.
- Unionized (lipophilic) forms are better absorbed across the lipid membranes.
- Ionized (hydrophilic) forms remain trapped in the aqueous phase and may be excreted.
Example: Aspirin (a weak acid) is better absorbed in the acidic stomach, while codeine (a weak base) is absorbed in the basic pH of the small intestine.
d. Lipophilicity and Partition Coefficient (Log P)
Lipophilicity, often expressed as the log P value, indicates the drug’s affinity for lipid membranes.
- Drugs with moderate lipophilicity (log P between 1 and 3) generally exhibit favorable absorption.
- Extremely lipophilic drugs may be sequestered in lipid bilayers, and excessively hydrophilic drugs may fail to permeate the membrane.
e. Molecular Weight and Size
The molecular size of a drug influences its ability to traverse biological membranes. Typically, compounds with molecular weights less than 500 Da exhibit better membrane permeability.
- Large molecules such as peptides and proteins are often degraded enzymatically or poorly absorbed due to size constraints.
- Innovative strategies such as prodrugs, lipid conjugation, and carrier-mediated transport are used to enhance the permeability of large molecules.
2. Physiological and Anatomical Factors
a. pH Variability in GIT
The GIT displays significant regional pH variation, impacting drug solubility and stability:
Stomach: pH 1.5–3.5 (acidic)
Duodenum: pH 5–6
Jejunum and Ileum: pH 6–7.5
Colon: pH 7–8
Drugs stable and soluble at specific pH ranges must be carefully formulated to ensure protection or timely release.
Example: Enteric-coated formulations bypass the stomach to protect acid-labile drugs like omeprazole.
b. Gastric Emptying and Intestinal Transit
The rate of gastric emptying determines how quickly the drug moves from the stomach to the small intestine, the primary site of absorption due to its vast surface area.
- Delayed gastric emptying slows absorption (e.g., after fatty meals, or under stress).
- Accelerated emptying can lead to premature drug degradation or reduced contact time.
The small intestine (with villi and microvilli) provides an extensive absorptive surface (~200–300 m²), while the colon, although less permeable, can absorb certain drugs through passive diffusion.
c. Gastrointestinal Motility
Abnormal intestinal motility can hinder absorption:
- Increased motility (e.g., in diarrhea) reduces drug residence time.
- Decreased motility (e.g., constipation or under influence of opioids) may increase absorption but also increase degradation.
d. Splanchnic Blood Flow
Blood flow to the GIT plays a pivotal role in maintaining the concentration gradient across the intestinal membrane, facilitating continuous absorption.
- After food intake, mesenteric blood flow increases, which may enhance drug absorption.
- Compromised perfusion in shock or sepsis can drastically reduce absorption efficiency.
3. Biochemical and Enzymatic Barriers
a. Digestive Enzymes and Brush Border Metabolism
Drugs administered orally are exposed to various proteolytic enzymes (e.g., pepsin, trypsin, chymotrypsin) and hydrolytic enzymes in the brush border.
- Peptides, proteins, and nucleotides are particularly susceptible.
- Enzyme inhibitors or protective coatings are used to prevent degradation.
b. Pre-systemic or First-Pass Metabolism
Drugs absorbed from the GIT enter the hepatic portal circulation and may be extensively metabolized in the liver before reaching systemic circulation.
- First-pass metabolism can significantly reduce drug bioavailability.
- This effect can be bypassed using sublingual, buccal, or rectal routes.
Example: Nitroglycerin is ineffective orally due to extensive first-pass metabolism.
4. Transport Mechanisms Across Intestinal Membrane
Suggested post: Absorption of drug in GIT
Drugs utilize different mechanisms to cross the epithelial barrier:
a. Passive Diffusion
Passive diffusion is the most common mechanism of drug absorption. It is driven by a concentration gradient, allowing substances to move from an area of higher concentration to one of lower concentration. This process is especially favored by molecules that are small, lipophilic, and unionized.
b. Facilitated Diffusion
Facilitated diffusion is a carrier-mediated transport mechanism that does not require energy. It involves the use of specific carrier proteins that recognize and bind to molecules based on their molecular structure, allowing them to cross the cell membrane along the concentration gradient.
c. Active Transport
Active transport is an energy-dependent mechanism that enables the absorption of substances against their concentration gradient. This process is both saturable and selective, meaning it relies on specific transporters that can become fully occupied at high substrate concentrations. An example of active transport is the absorption of levodopa, which utilizes large neutral amino acid transporters to cross cellular membranes.
d. Endocytosis and Pinocytosis
Endocytosis and pinocytosis are mechanisms involving the engulfment of particles or fluids into vesicles formed by the cell membrane. These processes are particularly important for the absorption of large or highly polar molecules that cannot cross the membrane by diffusion or transporters. For example, vitamin B12 is absorbed through endocytosis when bound to intrinsic factor.
5. Role of Transporters and Efflux Proteins
a. P-glycoprotein (P-gp)
P-glycoprotein (P-gp) functions as an efflux pump that actively transports drugs out of cells and back into the intestinal lumen. This action reduces the intracellular concentration of drugs and limits their systemic absorption. P-gp plays a significant role in drug resistance and bioavailability, with common substrates including digoxin, paclitaxel, and cyclosporine.
b. Organic Anion and Cation Transporters
Organic anion and cation transporters facilitate both the uptake and efflux of a wide range of drugs across cellular membranes. Their expression levels vary along different segments of the intestinal tract, and they are significantly influenced by genetic polymorphisms, which can affect drug response and pharmacokinetics in individuals.
6. Pharmaceutical and Formulation Factors
a. Dosage Form and Disintegration Rate
The design and composition of the dosage form heavily influence absorption:
- Solutions and suspensions exhibit faster absorption than tablets or capsules.
- Disintegration time affects how quickly the drug becomes available for absorption.
- Use of disintegrants, binders, and coatings modifies the disintegration and dissolution profiles.
b. Modified and Controlled-Release Formulations
- Designed to release the drug over an extended period.
- Reduce dosing frequency and improve compliance.
- Must ensure that the release rate matches the absorption window.
c. Excipients and Additives
- Surfactants enhance solubility.
- Buffers maintain optimal pH.
- Polymers control release.
7. Influence of Food and Gastrointestinal Contents
a. Positive Effects of Food
Food can have several positive effects on drug absorption. It enhances the solubility of lipophilic drugs by stimulating bile secretion, which aids in their dissolution. Additionally, food intake increases gastric retention time, offering a longer window for drug absorption in the gastrointestinal tract. For certain medications, food may also help reduce gastrointestinal irritation, improving overall patient comfort and compliance.
b. Negative Effects
Food can also have negative effects on drug absorption. It may delay the absorption of some drugs by slowing gastric emptying. Additionally, food components like dietary minerals can form complexes with certain drugs—such as tetracycline binding with calcium—reducing their bioavailability. Changes in gastric pH caused by food intake can further affect the solubility and stability of medications. Clinically, it is important to administer specific drugs either on an empty stomach or with food, depending on their known interaction profiles to ensure optimal therapeutic effectiveness.
8. Drug-Drug and Drug-Disease Interactions
a. Concomitant Medications
- Antacids and PPIs elevate gastric pH, affecting drugs requiring acidic conditions.
- Chelating agents bind with antibiotics like tetracyclines.
- Enzyme inducers/inhibitors affect first-pass metabolism.
b. Disease Conditions
- Gastrointestinal disorders (e.g., Crohn’s disease, ulcerative colitis) impair absorption.
- Liver diseases influence metabolism and protein binding.
- Renal dysfunction affects ion balance and transporter functions.
9. Influence of Gut Microbiota
The intestinal microbiota plays an emerging role in drug metabolism:
- Enzymatic biotransformation of certain drugs (e.g., sulfasalazine, digoxin).
- Inter-individual variation in microbiota composition may explain variable responses.
- Dysbiosis due to antibiotics can alter drug absorption patterns.
Conclusion
The process of drug absorption from the gastrointestinal tract is governed by a complex interplay of physicochemical properties, anatomical considerations, physiological functions, biochemical barriers, formulation strategies, and external influences such as food and other drugs. The oral route, while convenient, demands careful attention to these multifactorial variables to ensure optimal bioavailability, therapeutic efficacy, and patient compliance.
Advancements in drug delivery technologies, including nanoparticles, prodrugs, permeability enhancers, and smart polymers, are rapidly evolving to overcome these barriers. Personalized medicine and pharmacogenomics are also expected to play a significant role in tailoring drug therapies based on individual absorption characteristics.