Drug Elimination and Clearance

Drug elimination is the irreversible removal of a drug from the body, occurring through metabolism (chiefly hepatic biotransformation) and excretion (chiefly renal and biliary). Its central quantitative measure is clearance - the volume of plasma effectively cleared of drug per unit time. Clearance, together with the volume of distribution, is one of the two fundamental pharmacokinetic parameters and the primary determinant of the steady-state exposure achieved at a given dose rate.

Definition

Clearance is the proportionality constant relating the rate of drug elimination to the plasma concentration; equivalently, it is the volume of plasma from which drug is completely removed per unit time, and total clearance is the sum of the clearances by each eliminating organ.

Scope

This topic covers the organ and enzymatic routes of drug elimination, the concept and additivity of clearance, the distinction between intrinsic and organ clearance, and the influence of plasma protein binding and blood flow. It is framed as a pharmacokinetic and physicochemical topic, not as dosing guidance.

Core questions

• By what routes is a drug eliminated from the body?
• How is clearance defined, and why is it the key parameter for steady-state exposure?
• How do intrinsic clearance, protein binding, and organ blood flow combine to set organ clearance?

Key concepts

• Total (systemic) clearance
• Hepatic clearance
• Renal clearance
• Intrinsic clearance
• Extraction ratio
• Flow-limited vs capacity-limited elimination
• First-order vs zero-order (saturable) elimination
• Free fraction and microsomal binding

Key theories

Well-stirred (venous-equilibrium) model of hepatic clearance

Hepatic clearance is commonly described as a function of liver blood flow, the unbound fraction of drug, and intrinsic clearance; the model explains why high-extraction drugs are flow-limited while low-extraction drugs are limited by intrinsic clearance and binding, and underpins the prediction of clearance from in vitro data.

Mechanisms

A drug is eliminated when it is chemically transformed (metabolised) or physically removed (excreted). The liver biotransforms many drugs via cytochrome P450 and conjugating enzymes; the kidney excretes drug and metabolites by filtration, secretion, and reabsorption; and bile provides an additional route. Each organ's contribution is its clearance, and these add to give total clearance. For the liver, clearance can be related to blood flow, the unbound drug fraction, and intrinsic metabolic capacity: high-extraction drugs are limited mainly by blood flow, while low-extraction drugs are sensitive to changes in protein binding and enzyme activity. Apparent intrinsic clearance measured in vitro must be corrected for nonspecific binding in the assay to predict in vivo behaviour (Austin, 2002). Most drugs are eliminated by first-order kinetics, but saturable processes can produce zero-order, dose-dependent elimination. Across many drugs, total clearance varies widely and correlates with physicochemical and binding properties (Obach, 2008).

Clinical relevance

Clearance is the parameter that conceptually governs the maintenance dose rate needed to sustain a given steady-state exposure, and changes in clearance (for example with organ function or drug interactions) alter that exposure. This entry explains the concept and its determinants at a reference level and is not a basis for dosing or individualised treatment decisions.

Evidence & guidelines

In vitro-in vivo extrapolation of clearance from metabolic-stability assays is a standard part of drug development, provided assay binding is accounted for (Austin, 2002). Compendia of human pharmacokinetic parameters document the observed range of clearance values and their correlates, supporting expectations during candidate characterisation (Obach, 2008; Rowland & Tozer, 2011).

History

Clearance was adopted from renal physiology into pharmacokinetics in the twentieth century and was developed into a unifying framework relating organ blood flow, binding, and intrinsic metabolic capacity, formalised in texts such as Gibaldi and Perrier (1982). Later work focused on predicting clearance from in vitro metabolic data, including corrections for assay binding (Austin, 2002), and on mapping clearance across large drug datasets (Obach, 2008).

Key figures

• Malcolm Rowland
• Thomas Tozer
• R. Scott Obach
• Robert Austin
• Milo Gibaldi

Seminal works

• gibaldi-perrier-1982
• austin-2002
• obach-2008

Frequently asked questions

What is drug clearance?

Clearance is the volume of plasma from which a drug is completely removed per unit time. It summarises the body's overall efficiency at eliminating the drug and, together with the volume of distribution, determines the drug's half-life.

What is the difference between intrinsic clearance and organ clearance?

Intrinsic clearance reflects the inherent metabolic capacity of an organ's enzymes in the absence of blood-flow and binding limits. Organ clearance is what is actually achieved in the body, where blood flow to the organ and the unbound fraction of drug also constrain elimination.