Pharmacokinetics: Factors affecting drug absorption and pH partitioning theory

Introduction

Drug absorption represents the first and often most critical step in the journey from administration to therapeutic effect. It encompasses the processes by which a pharmaceutical compound traverses biological barriers, enters systemic circulation, and becomes available for interaction with target tissues. In the context of pharmacokinetics, absorption is frequently described by the equation F = (AUC × CL)/Dose, where F denotes absolute bioavailability, AUC the area under the plasma concentration–time curve, and CL systemic clearance. Historically, the concept of absorption evolved alongside the discovery of the gastrointestinal tract’s role in drug uptake, with early pharmacologists noting that orally administered agents could achieve therapeutic plasma concentrations comparable to those delivered via parenteral routes.

Understanding absorption is indispensable for both clinicians and pharmacists, as it directly influences dosing regimens, therapeutic efficacy, and the potential for adverse effects. The interplay between drug physicochemical properties, formulation characteristics, and physiological variables generates a complex landscape that must be navigated to optimize therapeutic outcomes.

Learning objectives:

• Define the fundamental parameters governing drug absorption.
• Explain the pH partitioning theory and its relevance to drug uptake.
• Identify key physiological and physicochemical factors that modulate absorption.
• Apply absorption principles to clinical scenarios involving formulation and patient variables.
• Evaluate strategies to enhance bioavailability in therapeutic practice.

Fundamental Principles

Core Concepts and Definitions

Absorption is generally categorized into two principal mechanisms: passive diffusion and active transport. Passive diffusion proceeds down a concentration gradient without direct energy expenditure, whereas active transport relies on carrier proteins and ATP-dependent processes. The extent of absorption is quantified by the fraction absorbed (f_a) and absolute bioavailability (F), where F = f_a × f_g × f_h, with f_g and f_h representing first-pass gastrointestinal and hepatic extraction ratios, respectively.

Theoretical Foundations

The pH partitioning theory, first articulated by Dr. George Stokes and later refined by Dr. Henry Grunwald, provides a framework for understanding how ionizable drugs cross biological membranes. According to this theory, the rate of passive diffusion is governed by the lipophilic, non-ionized fraction of a compound, which is determined by its pKa and the surrounding pH. The Henderson–Hasselbalch equation is frequently employed to estimate the percentage of drug in the non-ionized form:

Non‑ionized fraction (%) = 100 / (1 + 10^(pKa – pH)) (for bases) or 100 / (1 + 10^(pH – pKa)) (for acids).

Thus, drugs that are predominantly ionized at a given pH will exhibit reduced membrane permeability and, consequently, diminished absorption.

Key Terminology

• First-pass effect: The reduction in systemic availability of a drug due to metabolism in the gut wall and liver before reaching systemic circulation.
• Permeability surface area product (PS): A product of permeability coefficient (P) and surface area (S), representing the capacity of a membrane to absorb a drug.
• Solubility–permeability trade-off: The inverse relationship where highly soluble drugs often possess lower membrane permeability, and vice versa.
• Biopharmaceutics Classification System (BCS): A framework categorizing drugs into four classes based on solubility and intestinal permeability, which informs formulation strategies.

Detailed Explanation

Mechanisms and Processes

Drug molecules encounter multiple barriers during oral absorption: the luminal fluid, epithelial cell surface, intracellular cytoplasm, and the basolateral membrane. The lipophilic nature of the epithelial cell membrane is a critical determinant; non-ionized molecules partition into the membrane, traverse the lipid bilayer, and re-enter the lumen or blood side as ionized species. This process is described by the bilayer partition coefficient (K_lipid) and the diffusion coefficient (D).

Active transport mechanisms include carrier-mediated uptake via peptide transporters (PEPT1/2), glucose transporters (GLUT1/2), and nucleoside transporters (ENT1/2). Additionally, drug efflux pumps such as P-glycoprotein (P-gp) can limit absorption by actively exporting drugs back into the lumen.

Mathematical Relationships

Under steady-state conditions, the rate of absorption (R_a) can be expressed as:

R_a = P × A × (C_in – C_out)

where P is the permeability coefficient, A the absorptive surface area, and C_in and C_out the drug concentrations on either side of the membrane. The permeability coefficient itself is influenced by the drug’s solubility (S) and the membrane’s partition coefficient (K_lipid):

P = (D × K_lipid) / h

with h representing the membrane thickness. These equations collectively underscore the multi-factorial nature of absorption.

Factors Affecting the Process

Several interrelated factors modulate drug absorption, often acting in concert:

1. Physicochemical properties: Lipophilicity (logP), ionization status (pKa), molecular weight, and crystal lattice energy influence solubility and permeability.
2. Formulation characteristics: Particle size reduction, salt formation, use of surfactants, and solid dispersion techniques can enhance dissolution rate.
3. Gastrointestinal physiology: Gastric pH, gastric emptying time, intestinal transit time, and mucosal surface area vary with age, disease states, and concomitant medications.
4. Drug–drug interactions: Concomitant agents may alter gastric pH (e.g., proton pump inhibitors), inhibit or induce transporters, or compete for metabolic enzymes.
5. Pathophysiological conditions: Inflammatory bowel disease, celiac disease, and bariatric surgery can reduce absorptive surface area or alter pH profiles.
6. Food effects: High-fat meals can increase solubilization of lipophilic drugs but may delay gastric emptying, thereby prolonging absorption.

Clinical Significance

Relevance to Drug Therapy

Inadequate absorption can lead to subtherapeutic plasma concentrations, treatment failure, and the emergence of resistance, particularly in antimicrobial therapy. Conversely, excessive absorption may increase the risk of toxicity, as seen with drugs possessing narrow therapeutic indices.

Practical Applications

Formulators routinely employ the concepts of pH partitioning to select appropriate dosage forms. For instance, weakly basic drugs such as ranitidine are often formulated as enteric-coated tablets to protect them from acidic degradation in the stomach and to exploit their higher non-ionized fraction in the more neutral intestinal milieu. Weakly acidic drugs like ibuprofen may be formulated as salt forms to improve solubility in the acidic stomach.

Clinical Examples

• Amphotericin B: Poor oral absorption due to low solubility and permeability; thus, intravenous administration remains standard.
• Midazolam: Demonstrates high first-pass metabolism; however, its lipophilicity and low ionization ensure rapid absorption, making it suitable for inhalational and intranasal routes.
• Clopidogrel: Requires metabolic activation by CYP2C19; its absorption is unaffected by gastric pH but can be reduced by proton pump inhibitors that inhibit CYP activity.

Clinical Applications/Examples

Case Scenario 1: Proton Pump Inhibitor (PPI) Interaction

A 65-year-old patient on omeprazole therapy requires initiation of rabeprazole for ulcer prevention. Rabeprazole’s absorption is partially pH-dependent; however, omeprazole’s suppression of gastric acid may alter rabeprazole’s solubility profile. Clinical management would involve adjusting the timing of administration, possibly administering rabeprazole before omeprazole, or selecting an alternative agent with lesser pH dependence.

Case Scenario 2: Bariatric Surgery and Drug Absorption

A post‑Roux–en‑Y gastric bypass patient presents with inadequate glycemic control despite standard insulin dosing. Altered intestinal anatomy reduces absorptive surface area and modifies pH gradients, potentially impairing absorption of oral antidiabetic agents. Transitioning to a long‑acting insulin analog or a once‑daily oral agent with enhanced permeability may mitigate the issue.

Case Scenario 3: Bitter Drug Taste Masking

A pediatric formulation of chlorpheniramine is unpalatable due to its bitter taste. Incorporation of taste-masking agents such as cyclodextrins increases the drug’s solubility in the oral cavity, reducing the concentration of the free ionized drug that interacts with taste receptors. This strategy preserves systemic exposure while improving patient compliance.

Problem-Solving Approach

1. Identify the physicochemical profile of the drug: pKa, logP, molecular weight.
2. Assess the physiological context of the patient: GI pH, transit times, presence of disease.
3. Determine formulation strategy to optimize solubility/permeability balance (e.g., use of nanoparticles, solid dispersions).
4. Predict potential interactions with concomitant medications that may alter pH or transporter activity.
5. Monitor therapeutic levels and adjust dosing or formulation as necessary.

Summary/Key Points

• Drug absorption is governed by passive diffusion and active transport, with the pH partitioning theory providing a predictive framework for ionizable compounds.
• Key determinants include physicochemical properties, formulation attributes, gastrointestinal physiology, and drug–drug interactions.
• Mathematical models, such as the permeability coefficient equation, aid in quantifying absorption dynamics.
• Clinical implications span dose optimization, therapeutic monitoring, and formulation design to mitigate adverse interactions.
• Strategic manipulation of pH, solubility, and permeability can enhance bioavailability, particularly for drugs with narrow therapeutic windows or limited absorption.

Important Formulas

• Non‑ionized fraction (bases): 100 / (1 + 10^(pKa – pH))
• Non‑ionized fraction (acids): 100 / (1 + 10^(pH – pKa))
• Absorption rate: R_a = P × A × (C_in – C_out)
• Permeability coefficient: P = (D × K_lipid) / h
• Absolute bioavailability: F = f_a × f_g × f_h

Clinical Pearls

• Consider the ionic state of a drug when selecting the route of administration.
• Use enteric coatings or alkaline buffers to shield acid-labile drugs.
• Monitor for first-pass metabolism when prescribing drugs with known hepatic clearance.
• Adjust dosing schedules when co-administering agents that alter gastric pH or transporter activity.
• Employ formulation strategies such as salt formation or nanosuspensions to overcome solubility limitations.

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