6.23 : Hepatic Drug Clearance: Restrictive and Nonrestrictive Clearance

Hepatic clearance refers to the volume of blood cleared of a drug by the liver per unit of time. It plays a crucial role in drug metabolism and elimination. While hepatic clearance is commonly estimated by subtracting renal clearance from total body clearance, other pathways, such as pulmonary or biliary clearance, may also contribute. However, these pathways are generally less significant than hepatic and renal clearance.

Most drugs undergo restrictive clearance, which is proportional to the unbound (free) fraction of the drug. The unbound fraction is the active form of the drug available for metabolism and elimination. When highly protein-bound drugs are displaced from their protein-binding sites, their clearance substantially increases, often reaching levels comparable to low-protein-binding drugs.

Conversely, nonrestrictive clearance applies to liver-derived drugs regardless of their protein binding. These drugs are more easily separated from the protein during metabolism. As a result, their clearance is not primarily dependent on protein binding characteristics.

Hepatic blood flow, intrinsic clearance, and protein binding share a proportional relationship for restrictively cleared drugs. Intrinsic clearance refers to the rate at which the liver enzymes metabolize the drug. If the intrinsic clearance is smaller than the hepatic blood flow, hepatic clearance is mainly determined by the intrinsic clearance of both the free and bound forms of the drug. However, if the intrinsic clearance surpasses the hepatic blood flow, the equation simplifies, and hepatic clearance becomes primarily dependent on the hepatic blood flow.

Understanding the factors influencing hepatic clearance is important in pharmacokinetics and drug dosing. Hepatic clearance helps determine the rate at which drugs are eliminated from the body. Factors such as protein binding, hepatic blood flow, and intrinsic clearance contribute to the overall hepatic clearance of a drug.