Most drugs follow linear pharmacokinetics, where the drug concentration increases in direct proportion to the dose. However, some drugs behave differently and show non-linear pharmacokinetics. In this case, small changes in dose may produce disproportionately large changes in blood levels. This often occurs when processes like metabolism, protein binding, or transport become saturated.
What Is Non-Linear Pharmacokinetics?
Non-linear pharmacokinetics refers to situations where drug concentration does not increase proportionally with dose. It is also called dose-dependent or capacity-limited pharmacokinetics.
Example: Doubling the dose does not double the concentration; it may increase it two or three times more.
Why Does Non-Linearity Occur?
Non-linearity occurs when one or more processes involved in ADME become saturated.
Key Saturable Processes
- Saturable metabolism: enzymes reach maximum capacity
- Saturable protein binding: binding sites become full
- Saturable absorption: limited transport carriers
- Saturable renal secretion: transporters overloaded
Michaelis–Menten Kinetics
Non-linear pharmacokinetics is often explained using the Michaelis–Menten equation. It describes how enzymes metabolize drugs when capacity becomes limited.
Equation
v = (Vmax · C) / (Km + C)
Where:
- v = rate of metabolism
- C = drug concentration
- Vmax = maximum metabolic rate
- Km = concentration at which metabolism is half of Vmax
When Does Non-Linearity Become Prominent?
- When drug concentration is near or above Km
- When metabolic enzymes are saturated
Characteristics of Non-Linear Pharmacokinetics
- Half-life changes with dose (longer at high doses)
- Clearance decreases when dose increases
- Non-proportional rise in plasma concentration
- Risk of accumulation and toxicity
- Steady state becomes unpredictable
Types of Non-Linearity
1. Saturable Metabolism
Occurs in drugs such as:
- Phenytoin
- Ethanol
- Aspirin (high doses)
2. Saturable Protein Binding
At high concentrations, binding sites become full, increasing free drug levels.
3. Saturable Absorption
Limited carriers cause decreased absorption at high doses.
4. Saturable Renal Excretion
Transport mechanisms in kidneys become overloaded.
Clinical Examples
1. Phenytoin
- Classic example of non-linear kinetics
- Small dose increases → large rise in levels
- Requires therapeutic drug monitoring
2. Ethanol
At moderate to high concentrations, alcohol metabolism becomes saturated, leading to zero-order elimination.
3. Salicylates
High doses saturate metabolism and increase toxicity risk.
Clinical Importance of Non-Linear Pharmacokinetics
1. Dose Adjustments Must Be Made Carefully
Small increases in dose may produce toxic levels.
2. Narrow Therapeutic Window Drugs Require Monitoring
Example: phenytoin requires regular plasma level checks.
3. Toxicity May Occur Suddenly
Because elimination becomes saturated, drug accumulation is rapid.
4. Steady State Is Difficult to Predict
Unlike linear drugs, steady state may not follow normal rules.
5. Clearance Is Not Constant
Clearance decreases with increasing concentration, making kinetics unpredictable.
Graphical Features
- Plasma concentration rises disproportionately at higher doses
- Curve becomes curved, not a straight line
- Half-life increases as dose increases
When to Suspect Non-Linearity
- If doubling the dose causes more than double increase in plasma concentration
- If half-life increases with dose
- If toxicity appears unexpectedly after minor dose changes
Detailed Notes:
For PDF style full-color notes, open the complete study material below:
PATH: PHARMD/ PHARMD NOTES/ PHARMD FOURTH YEAR NOTES/ BIOPHARMACEUTICS AND PHARMACOKINETICS/ NON LINEAR PHARMACOKINETICS.
