Clearance and Elimination

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