Pharmacokinetics: Mapping the Body's Response to Xenobiotics

➡️ Absorption

Absorption is the process by which a drug enters the systemic circulation from its site of administration. This phase is critical for determining the rate and extent of drug exposure. Factors influencing absorption include the drug's formulation, route of administration, and physiological characteristics of the absorption site.

🗺️ Distribution

Distribution describes the reversible dispersion of a drug throughout the body's fluids and tissues. Once absorbed, drugs distribute from the bloodstream to various tissues and organs. This process is influenced by factors such as blood flow, tissue permeability, plasma protein binding, and the drug's physicochemical properties (e.g., lipophilicity).

🔄 Metabolism (Biotransformation)

Metabolism involves the chemical alteration of drugs, primarily occurring in the liver via enzymatic reactions (e.g., cytochrome P450 enzymes). This process typically converts drugs into more polar metabolites, facilitating their excretion. Metabolism can lead to drug inactivation, activation (prodrugs), or the formation of active metabolites.

🚽 Excretion (Elimination)

Excretion is the irreversible removal of drugs and their metabolites from the body. The primary route is via the kidneys (urine), but other routes include the bile (feces), lungs, sweat, and saliva. Elimination kinetics determine the drug's duration of action and the time required to clear it from the system.

📦 Liberation

Liberation, often considered the initial step (LADME), refers to the release of the active pharmaceutical ingredient from its dosage form (e.g., tablet, capsule) before absorption can occur. The rate and extent of liberation are heavily dependent on the formulation's design and dissolution characteristics.

💻 Conceptualizing Drug Dynamics

Pharmacokinetic modeling simplifies the complex interactions between the body and chemical substances. These models, often represented by mathematical equations and graphical plots, help predict drug behavior based on its properties (e.g., pKa, solubility, absorption characteristics).

Common approaches include non-compartmental analysis (NCA), which directly analyzes concentration-time data using methods like the trapezoidal rule, and compartmental analysis, which uses differential equations to represent drug distribution and elimination.

📦 Compartmental Models

Compartmental models simplify the body into distinct compartments representing tissues with similar drug distribution characteristics.

• Single-Compartment Model: Assumes the body acts as a single, homogenous unit. Plasma concentration is directly related to drug concentration in all tissues. Elimination often follows first-order kinetics (linear pharmacokinetics).
• Two-Compartment Model: Divides the body into a central compartment (well-perfused organs like blood, liver, kidneys) and a peripheral compartment (less perfused tissues). This accounts for slower distribution phases.
• Multi-Compartment Models: Extend this concept to include numerous compartments, providing a more detailed, albeit complex, representation of drug distribution across diverse tissues. Physiologically-based pharmacokinetic (PBPK) models are highly sophisticated examples.

📉 Non-Linear Kinetics

Non-linear pharmacokinetics occurs when processes like absorption, distribution, metabolism, or excretion become saturated at higher drug concentrations. This deviates from first-order kinetics, often following Michaelis-Menten principles.

Key indicators of non-linearity include:

• Multiphasic elimination: Initial rapid decline (distribution phase, alpha) followed by slower elimination (beta phase).
• Enzyme saturation: Metabolic enzymes become overwhelmed, leading to disproportionate increases in plasma concentration with dose escalation.
• Enzyme induction/inhibition: Drugs altering their own metabolism or that of other drugs.

🧪 Bioanalytical Methods

Accurate measurement of drug concentrations in biological matrices (typically plasma) is essential for PK studies. Bioanalytical methods must be selective and sensitive.

Techniques like Liquid Chromatography-Mass Spectrometry (LC-MS/MS) are widely used due to their sensitivity and specificity, allowing quantification even at low concentrations over extended periods. Standard curves and internal standards are critical for accurate quantitation.

💡 Microdosing and SESI-MS

Microdosing involves administering ultra-low, sub-pharmacological doses of a drug to human subjects early in development. This approach, often utilizing highly sensitive mass spectrometry techniques like Secondary Electrospray Ionization-Mass Spectrometry (SESI-MS), can provide early PK data while minimizing exposure and potentially reducing the need for animal testing.

💊 Therapeutic Drug Monitoring (TDM)

Clinical pharmacokinetics applies PK principles directly to patient care, often through Therapeutic Drug Monitoring (TDM). TDM involves measuring drug concentrations in a patient's plasma to guide dosage adjustments, particularly for drugs with a narrow therapeutic index, high toxicity, or significant inter-individual variability.

Examples of drugs commonly monitored include certain antiepileptics (e.g., Phenytoin), immunosuppressants (e.g., Ciclosporin), cardiac drugs (e.g., Digoxin), and antibiotics (e.g., Vancomycin).

⚙️ Case Study: Ciclosporin

The immunosuppressant Ciclosporin exemplifies the importance of clinical PK. Initially underutilized due to nephrotoxicity concerns, its therapeutic application was revitalized through TDM. By individualizing doses based on measured plasma concentrations, clinicians could maintain therapeutic efficacy while mitigating adverse effects, enabling successful organ transplantation.

📜 References