Difference between linear and non-linear pharmacokinetics in column form
Reading File
Finding Sources
Finding Sources
Reading File
Reading File
Reading File
Searching PubMed
nonlinear pharmacokinetics saturable metabolism
Linear vs Non-Linear Pharmacokinetics
| Feature | Linear Pharmacokinetics | Non-Linear Pharmacokinetics |
|---|---|---|
| Also called | First-order kinetics | Zero-order kinetics / saturation (Michaelis-Menten) kinetics |
| Basic principle | Rate of drug elimination is proportional to plasma drug concentration | Rate of drug elimination is constant, independent of plasma concentration, because the elimination pathway is saturated |
| Governing equation | dA(t)/dt = -k₁·A(t), giving C(t) = C₀·e^(-kt) (exponential decline) | dA(t)/dt = -k₀ (constant), or Michaelis-Menten: rate = Vmax·C/(Km + C) |
| Fraction of drug eliminated per unit time | Constant fraction eliminated per unit time (e.g., a fixed half-life) | Constant amount (not fraction) eliminated per unit time; half-life is not constant |
| Half-life (t½) | Constant, independent of dose or concentration | Not constant - increases as dose/concentration increases (apparent half-life lengthens) |
| Relationship between dose and plasma concentration | Steady-state plasma concentration rises proportionally with dose | Small dose increases can cause disproportionately large rises in plasma concentration once capacity is saturated |
| Clearance | Constant, independent of dose or concentration | Decreases as concentration rises (capacity-limited) |
| AUC (area under curve) | Increases proportionally with dose | Increases more than proportionally with dose beyond the saturation point |
| Underlying mechanism | Elimination pathways (metabolism/renal transport) have abundant unsaturated capacity relative to drug concentration | Metabolic enzymes or transporters become saturated at concentrations used clinically or in overdose |
| Predictability of dosing | Dose adjustments are simple and predictable (linear relationship) | Small dose changes near the saturation point can produce unpredictable, large swings in concentration - narrow margin between therapeutic and toxic doses |
| Typical drug examples | Most drugs at usual therapeutic doses (e.g., aminoglycosides, digoxin, most beta-blockers) | Phenytoin, ethanol, salicylates (at high/toxic concentration), theophylline (at higher doses) |
| Clinical example | Increasing a stable drug's dose from 100 mg to 200 mg roughly doubles steady-state plasma level | In phenytoin, increasing dose modestly beyond the saturation threshold can markedly increase levels, risking toxicity; in salicylates, elimination is first-order below ~30 mg/dL but becomes zero-order (saturated) above it |
| Graphical pattern | Semi-log plot of concentration vs. time is a straight line | Semi-log plot curves; at high concentrations the decline looks closer to linear (constant amount/time) rather than an exponential curve |
Key textbook explanation
- First-order (linear) kinetics: "For most drugs in their therapeutic concentration ranges, the amount of drug metabolized per unit time is proportional to the plasma concentration of the drug (C) and the fraction of drug removed by metabolism is constant." - Goodman & Gilman's Pharmacological Basis of Therapeutics
- Zero-order (non-linear) kinetics: "For some drugs, such as ethanol and phenytoin, metabolic capacity is saturated at the concentrations usually employed, and drug metabolism becomes zero order; that is, a constant amount of drug is metabolized per unit time. Zero-order kinetics can also occur at high (toxic) concentrations as drug-metabolizing capacity becomes saturated." - Goodman & Gilman's Pharmacological Basis of Therapeutics
- Similarly, Katzung's notes that with phenytoin, "as the dose increases, there is saturation of metabolism and a shift from first-order to zero-order kinetics, in which a constant quantity per unit time is eliminated" - Katzung's Basic and Clinical Pharmacology, p. 883-890
- Rosen's Emergency Medicine gives the salicylate example: "At therapeutic salicylate concentrations, elimination follows first-order kinetics. Once serum salicylate concentrations are greater than 30 mg/dL, elimination follows zero-order kinetics" as metabolic pathways saturate - Rosen's Emergency Medicine
Clinical significance
Non-linear kinetics matters most for drugs with a narrow therapeutic index that undergo saturable metabolism (phenytoin being the classic teaching example). Because a small dose increase can produce a disproportionate rise in plasma concentration once saturation occurs, dose titration must be done cautiously and with therapeutic drug monitoring near the saturation threshold - unlike linear-kinetic drugs, where dose and plasma concentration change proportionally and are easier to predict.
This is a shared conversation. Sign in to Orris to start your own chat.