Principles of Pharmacokinetics and Drug Absorption

Posted on Jul 24, 2026 in Biotechnology

1. Gastrointestinal Tract (GIT) Drug Absorption

Gastrointestinal tract (GIT) drug absorption relies on several physiological mechanisms. Key factors like molecular size, lipid solubility, gastrointestinal pH, and gastric emptying time heavily influence how quickly and completely a medication enters the systemic circulation.

Mechanisms of Drug Transport

Drugs traverse the gastrointestinal membrane primarily through the following pathways:

• Passive Diffusion: The most common mechanism. Drugs move naturally from a region of high concentration in the gut lumen to a region of lower concentration in the blood. It does not require energy and is primarily driven by a drug’s lipid solubility (lipophilicity).
• Carrier-Mediated Transport: Specialized proteins on the cell membrane act as “ferries” to transport certain drug molecules across.
• Facilitated Diffusion: Moves drugs down their concentration gradient without energy, but at a faster rate using a carrier.
• Active Transport: Uses cellular energy (ATP) to move drugs against their concentration gradient or to speed up movement.
• Endocytosis: The cell membrane engulfs the drug molecule and pinches off to bring it inside as a vesicle. This includes pinocytosis (cell drinking) for liquids and phagocytosis (cell eating) for solids.
• Paracellular Transport: Drugs slip through the tiny spaces or “tight junctions” between adjacent intestinal cells. This is usually restricted to very small, water-soluble molecules.

Factors Affecting Gastrointestinal Transport

• Physicochemical properties: Lipid-soluble (hydrophobic), small-molecule drugs diffuse easily, while highly ionized, large, or water-soluble drugs have difficulty penetrating lipid membranes.
• Gastrointestinal pH: Weakly acidic drugs are unionized (neutral) in the acidic stomach, promoting absorption. Conversely, basic drugs are unionized in the slightly alkaline intestine.
• Gastric Emptying Time: How quickly the stomach empties its contents into the small intestine dictates how fast an oral drug is absorbed. Slower emptying typically delays drug absorption.
• Intestinal Motility: Faster bowel movements leave less time for a drug to be absorbed.
• First-Pass Metabolism: Drugs absorbed through the GIT travel directly to the liver, where enzymes may break down a significant portion of the active ingredient before it reaches the rest of the body.

2. Linear vs. Non-Linear Pharmacokinetics

Pharmacokinetics is how the body acts on a drug, summarized by Absorption, Distribution, Metabolism, and Excretion (ADME).

• Linear Pharmacokinetics: The drug’s concentration in the plasma increases in direct proportion to the administered dose. Key parameters like clearance (Cl), elimination half-life (t_1/2), and volume of distribution (V_d) remain constant regardless of the dose taken. The drug follows first-order kinetics.
• Non-Linear (Dose-Dependent) Pharmacokinetics: The drug concentration in the plasma does not increase proportionally with the dose. Doubling the dose may result in a much larger—or much smaller—plasma concentration than expected. Pharmacokinetic parameters change depending on the dose size. The drug follows a mix of first-order and zero-order kinetics.

Reasons for Non-Linearity

Non-linearity occurs when specialized physiological processes in the body reach their maximum capacity and become saturated:

1. Enzyme Saturation: Metabolic enzymes get “overloaded.” When an enzyme reaches its maximum working capacity (V_max), metabolism slows down, and plasma drug levels spike rapidly (e.g., the antiepileptic drug Phenytoin).
2. Carrier Saturation: Carrier-mediated transporters used for absorption or renal excretion get entirely filled.
3. Protein Binding Saturation: If a drug strongly binds to plasma proteins, the binding sites can become fully occupied. Excess free drug remains in the blood, inflating the apparent volume of distribution and altering clearance rates.
4. Pathological Alterations: Diseases (like kidney or liver failure) can impair the body’s natural ability to clear a drug.

3. Kinetics of Protein Binding

When drugs enter the bloodstream, a portion of the drug binds to plasma proteins (e.g., Albumin, Alpha-1-acid glycoprotein). The remaining unbound (“free”) drug is what exerts pharmacological effects, distributes into tissues, and gets eliminated. Protein binding is a reversible, dynamic equilibrium.

Significance of Protein Binding

• Drug Reservoir: Bound drugs act as a storage depot. As free drug is eliminated, the bound drug dissociates to maintain equilibrium, extending the duration of action.
• Restricts Distribution: Large proteins cannot easily cross capillary walls; therefore, highly protein-bound drugs remain confined to the bloodstream longer.
• Drug Interactions: If two drugs compete for the same binding protein, one may displace the other, increasing the concentration of free drug and potentially causing toxicity.

4. Drug Metabolism

Drug metabolism (biotransformation) is the chemical alteration of drugs in the body, primarily occurring in the liver. Its main goal is to convert fat-soluble (lipophilic) drugs into water-soluble (hydrophilic) forms for excretion.

Metabolic Pathways

• Phase I (Functionalization): Modifies the drug by adding or unmasking polar functional groups (e.g., -OH, -NH₂) via oxidation, reduction, or hydrolysis, often driven by the Cytochrome P450 (CYP450) system.
• Phase II (Conjugation): Attaches large, polar, endogenous molecules to the drug (e.g., glucuronidation, sulfation, acetylation) to create an inactive, water-soluble molecule ready for excretion.

5. Drug Excretion and Kinetics

Drug excretion is the irreversible removal of a drug or its metabolites from the body, primarily through the kidneys (urine) or liver (bile).

Renal Excretion Mechanisms

• Glomerular Filtration: Small, unbound drug molecules pass from the blood into the kidney’s urine filtrate.
• Active Tubular Secretion: Carrier proteins actively push drugs from the blood into the urine.
• Tubular Reabsorption: Fat-soluble drugs can diffuse back into the bloodstream from the urine.

Elimination Kinetics

• First-Order Kinetics: The rate of elimination is proportional to the amount of drug present. A constant fraction is removed per unit of time.
• Zero-Order Kinetics: The rate of elimination is constant, independent of drug concentration (e.g., high-dose alcohol or phenytoin).

6. Bioavailability: Measurement and Enhancement

Bioavailability refers to the rate and extent to which an active drug reaches the systemic circulation in its unchanged form.

Enhancement Techniques

• Particle Size Reduction: Increases surface area to speed up dissolution.
• Use of Surfactants: Lowers surface tension to improve wetting.
• Salt Formation: Increases aqueous solubility.
• Solid Dispersions: Prevents drug clumping in a carrier matrix.
• Enzyme Inhibitors: Limits premature metabolism in the gut.
• Lipid Formulations: Enhances absorption and bypasses the first-pass effect.

7. Two-Compartment Open Model

The body is divided into a Central Compartment (highly perfused tissues) and a Peripheral Compartment (poorly perfused tissues). The “open” model implies the drug can be eliminated from the system.

Plasma Concentration-Time Graph

Plotting plasma concentration against time on a semi-logarithmic scale yields a biphasic curve:

• Phase 1 (Distribution Phase / α-phase): Rapid decline as the drug moves from the central to the peripheral compartment.
• Phase 2 (Elimination Phase / β-phase): Slower decline once equilibrium between compartments is reached.

8. Pharmacokinetic Terms (One-Compartment IV)

• Elimination Rate Constant (k): The first-order rate at which a drug is irreversibly removed.
• Elimination Half-Life (t_1/2): The time required for the plasma drug concentration to decrease by 50%.
• Absorption Rate Constant (k_a): The rate at which a drug enters systemic circulation (not applicable to IV bolus).

9. Applications of Biopharmaceutics

Comparison Table

Clinical and Formulation Utility

• Formulation: Optimizes salt forms, particle sizes, and controlled-release designs.
• Clinical: Enables Therapeutic Drug Monitoring (TDM) and patient-specific dosing based on renal and hepatic function.

10. Level A Correlation and Wagner-Nelson Method

Level A IVIVC

This represents a point-to-point relationship between the entire in-vitro dissolution curve and the entire in-vivo input curve. It is the highest level of correlation recognized by regulatory agencies like the FDA, allowing in-vitro tests to serve as a surrogate for human bioequivalence studies.

Wagner-Nelson Method

A mathematical model used to calculate the cumulative fraction of drug absorbed over time from plasma concentration data, assuming a one-compartment open model.