Clearance and Elimination
How the body removes drugs through hepatic and renal clearance, and the relationship between clearance and steady-state levels.
## What Is Clearance?
Clearance (CL) is the volume of plasma from which drug is completely removed per unit time (typically mL/min or L/hr). It is the single most important pharmacokinetic parameter because it determines steady-state drug concentrations:
**Css = Dose rate / CL**
Total systemic clearance is the sum of all elimination routes:
**CL(total) = CL(renal) + CL(hepatic) + CL(other)**
## Hepatic Clearance
The liver eliminates drugs through metabolism (Phase I/II reactions) and biliary excretion. Hepatic clearance depends on three factors:
- **Hepatic blood flow (Q)**: normally ~1,500 mL/min
- **Intrinsic clearance (CL,int)**: the liver's inherent metabolic capacity
- **Fraction unbound (fu)**: only free drug is available for metabolism
The well-stirred model relates these:
**CL(hepatic) = Q x (fu x CL,int) / (Q + fu x CL,int)**
### High-Extraction Drugs (E > 0.7)
For drugs like lidocaine, propranolol, and morphine, hepatic clearance approaches liver blood flow. Their elimination is **flow-dependent** — changes in cardiac output or hepatic blood flow directly alter clearance. Protein binding changes have minimal effect.
### Low-Extraction Drugs (E < 0.3)
For drugs like warfarin, diazepam, and phenytoin, clearance is **capacity-dependent** — determined by intrinsic metabolic capacity and protein binding. Changes in blood flow have little effect, but enzyme induction/inhibition and protein binding shifts are significant.
## Renal Clearance
Renal clearance combines filtration, secretion, and reabsorption:
**CL(renal) = (GFR x fu) + CL(secretion) - CL(reabsorption)**
Drugs cleared primarily by the kidney (digoxin, metformin, lithium, aminoglycosides) require dose reduction in renal impairment, guided by CrCl or eGFR.
## Extraction Ratio
The extraction ratio (E) quantifies the fraction of drug removed during a single pass through an organ:
**E = (C,in - C,out) / C,in**
An extraction ratio of 0.9 means 90% of drug is removed per pass. This concept links clearance to organ blood flow: CL = Q x E.
## First-Order vs Zero-Order Elimination
- **First-order**: a constant fraction is eliminated per unit time. Most drugs at therapeutic doses. Rate increases proportionally with concentration.
- **Zero-order**: a constant amount is eliminated per unit time. Occurs when metabolic enzymes are saturated (ethanol, high-dose phenytoin, aspirin overdose). Dangerous because small dose increases cause disproportionate concentration rises.
## Key Takeaways
- Clearance is the most important parameter for determining maintenance dose
- Hepatic clearance is either flow-dependent (high extraction) or capacity-dependent (low extraction)
- Renal clearance requires dose adjustment as kidney function declines
- First-order elimination applies to most drugs at therapeutic doses
- Zero-order elimination is clinically dangerous due to nonlinear accumulation