Capacity-Limited Elimination and Dose Doubling
When the dose of a drug with capacity-limited (saturable, nonlinear) elimination is doubled, the half-life increases because the elimination pathways become progressively saturated, causing the drug to persist longer in the body.
Understanding Capacity-Limited Elimination
Capacity-limited elimination, also known as saturable or nonlinear pharmacokinetics, occurs when elimination mechanisms (typically enzymatic metabolism) become saturated at therapeutic doses 1. Unlike first-order kinetics where elimination rate is proportional to drug concentration, capacity-limited elimination follows Michaelis-Menten kinetics 1.
What Happens When Dose is Doubled
C) Half-life INCREASES ✓
- Half-life increases because as the dose increases and saturates elimination pathways, the drug is eliminated more slowly relative to the amount present 2
- In capacity-limited elimination, half-life is dose-dependent rather than constant 2
- The time required for plasma concentration to fall by 50% becomes progressively longer as initial concentrations increase 3
B) Rate of Elimination INCREASES (but disproportionately)
- The absolute rate of elimination does increase when dose is doubled, but not proportionally 1
- At saturation, the elimination rate approaches a maximum (Vmax) and cannot increase further despite higher doses 1
- This is why capacity-limited kinetics is problematic—small dose increases can lead to disproportionately large increases in drug exposure 1
A) Clearance DECREASES
- Clearance decreases as dose increases in capacity-limited elimination 1
- Clearance (volume of blood cleared per unit time) is dose-dependent in nonlinear kinetics, unlike first-order elimination where it remains constant 1
- As elimination pathways saturate, less drug is cleared per unit time relative to the amount present 1
D) Volume of Distribution (Vd) - NO CHANGE
- Volume of distribution is determined by drug physicochemical properties and tissue binding, not by dose 1
- Vd remains essentially constant regardless of dose changes 1
- Distribution characteristics are independent of elimination capacity 1
Clinical Implications
- Drugs with capacity-limited elimination require careful dose titration because small increases can cause disproportionate accumulation 1
- Examples include phenytoin, aspirin at high doses, and alcohol 1
- Toxicity monitoring becomes critical as doses approach saturation levels 1
- The relationship between dose and steady-state concentration becomes nonlinear and unpredictable 1
Answer: C) Half-life
The half-life increases when the dose of a capacity-limited elimination drug is doubled because elimination mechanisms become progressively saturated, causing slower relative elimination 2, 3.