Drug Elimination and Clearance

Elimination is the irreversible loss of a drug from the body, accomplished by excretion of unchanged drug (chiefly by the kidneys) and by metabolism. Clearance is the parameter that quantifies elimination: it is the volume of plasma cleared of drug per unit time and is the single parameter that determines a drug's total exposure for a given dose.

Definition

Clearance is the proportionality constant relating the rate of drug elimination to the plasma concentration; operationally, it is the volume of plasma from which drug is completely removed per unit time, and total body clearance is the sum of the clearances of all eliminating organs.

Scope

This topic covers how drugs leave the body — renal excretion and hepatic metabolism as the principal routes — and the clearance parameter that summarises elimination capacity. It addresses the additivity of organ clearances, the physiological model of hepatic clearance, and the role of renal function estimation. It is conceptual and educational and offers no dosing instructions.

Core questions

• By what routes — renal, hepatic, and other — is a given drug eliminated?
• Why is clearance the parameter that controls steady-state exposure rather than half-life?
• How do organ blood flow, intrinsic clearance, and protein binding shape hepatic elimination?
• How is renal function quantified when reasoning about renally cleared drugs?

Key concepts

• Total body (systemic) clearance
• Additivity of organ clearances
• Renal clearance (filtration, secretion, reabsorption)
• Hepatic clearance and extraction ratio
• Intrinsic clearance
• Glomerular filtration rate and its estimation
• Enterohepatic recirculation
• Flow-limited versus capacity-limited elimination

Mechanisms

Clearance expresses the body's overall ability to eliminate a drug and is the only pharmacokinetic parameter that controls total drug exposure at a given dose (Rowland, Benet & Graham, 1973; Toutain & Bousquet-Mélou, 2004). Because different organs eliminate drug in parallel, total clearance is the sum of renal, hepatic, and other organ clearances. Hepatic clearance depends on liver blood flow, the intrinsic metabolic capacity of hepatic enzymes, and the unbound fraction of drug; for high-extraction drugs it is limited by blood flow and for low-extraction drugs by enzyme activity (Wilkinson & Shand, 1975). Renal elimination combines glomerular filtration, active tubular secretion, and reabsorption, so estimating glomerular filtration rate is central to characterising renally cleared drugs (Levey et al., 2009). Some drugs and metabolites are secreted in bile, reabsorbed from the gut, and returned to the circulation — enterohepatic recirculation — which can prolong their persistence (Roberts et al., 2002).

Clinical relevance

Clearance is the parameter that links maintenance dosing to average steady-state concentration, and impaired renal or hepatic function reduces clearance and increases exposure. This entry explains the determinants of elimination so that such reasoning can be understood; it describes principles and is not a basis for adjusting doses for any individual.

Evidence & guidelines

Estimation of glomerular filtration rate using validated creatinine-based equations (Levey et al., 2009) underpins renal-function assessment in pharmacokinetic reasoning and in regulatory guidance on dosing in renal impairment. The physiological clearance model (Wilkinson & Shand, 1975) and the foundational clearance concepts (Rowland et al., 1973) are codified in clinical pharmacokinetics references.

History

Clearance was established as the central organising parameter of pharmacokinetics in the early 1970s (Rowland, Benet & Graham, 1973), and the physiological dependence of hepatic clearance on blood flow and intrinsic activity was formalised shortly after (Wilkinson & Shand, 1975). On the renal side, successive estimating equations for glomerular filtration rate, culminating in the CKD-EPI equation (Levey et al., 2009), refined how renal elimination capacity is quantified.

Key figures

• Malcolm Rowland
• Leslie Z. Benet
• Grant R. Wilkinson
• Andrew S. Levey
• Pierre-Louis Toutain

Seminal works

• rowland-1973
• wilkinson-shand-1975
• levey-2009

Frequently asked questions

Why is clearance, not half-life, said to control drug exposure?

Clearance directly relates the rate of elimination to plasma concentration, so for a given dosing rate it determines the average steady-state concentration and total exposure. Half-life is a derived parameter that depends on both clearance and volume of distribution.

What are the main routes of drug elimination?

The principal routes are renal excretion of unchanged drug and hepatic metabolism, with biliary excretion and other organs contributing for some drugs. Total body clearance is the sum of the clearances achieved by all eliminating organs.