Factors Causing Nonlinear Pharmacokinetics

Factors Causing Nonlinear Pharmacokinetics include enzyme saturation, protein binding, transport limits, and metabolic pathway shifts.

Nonlinear pharmacokinetics arises from the saturation of physiological processes involved in drug metabolism, absorption, distribution, or excretion.
Key mechanisms include:
1. Saturable Metabolism (Capacity-Limited Metabolism)
  - Enzymes (e.g., CYP450, alcohol dehydrogenase) become saturated at high drug concentrations.
  - Once saturation occurs, elimination shifts from first-order (proportional) to zero-order (constant rate).
  - Examples: Phenytoin, ethanol, theophylline, high-dose salicylates.
2. Saturable (Active) Transport
  - Active transporters (e.g., intestinal or renal) reach capacity at high doses, limiting absorption or excretion.
3. Saturable Plasma Protein Binding
  - At high drug concentrations, plasma protein binding sites become saturated, increasing free drug levels disproportionately.
  - Example: High-dose salicylates exhibit saturable albumin binding.
4. Enzyme Induction or Inhibition
  - Induction increases metabolism, reducing plasma drug levels over time.
  - Inhibition slows metabolism, increasing drug concentrations.
  - Can cause time-dependent nonlinearity.
5. Physiological Constraints
  - Changes in organ blood flow (e.g., liver, kidneys).
  - Physiological shifts due to high doses (e.g., pH changes, fluid distribution).