Hepatic Drug Clearance: Effect of Protein Binding

Hepatic clearance can be affected by protein binding based on the extraction ratio of the drug.

Drugs with high extraction ratios are flow-limited and unaffected by protein binding during hepatic clearance.

Drugs with low extraction ratios may be influenced by plasma protein binding, but the impact depends on the fraction of drug bound.

For low extraction ratio drugs that are less than 80% protein-bound, small changes in protein binding have minimal effects on hepatic clearance. These drugs are considered capacity-limited and binding-insensitive.

However,  those that are highly bound to plasma protein are considered capacity-limited and binding-sensitive. Small changes in protein binding can cause a significant increase in the free drug concentration, leading to an increased drug metabolism rate and hepatic clearance.

Any drug metabolized and eliminated by the liver can be classified by plotting on a triangular graph based on its extraction ratio and percent of plasma protein binding.