13.16: Effect of Hepatic Disease on Pharmacokinetics: Active Drug, Metabolite and Fraction of Metabolized Drug

In pharmacotherapy, monitoring drug concentrations is paramount, especially for drugs whose therapeutic effects hinge on both the active compound and its metabolite. Hepatic impairment profoundly influences drug potency by altering liver function. If the drug is more potent than its metabolite, impaired liver function amplifies drug activity due to elevated drug concentration levels. Conversely, if the metabolite holds greater potency, diminished liver function diminishes drug activity by hampering metabolite formation.

Moreover, hepatic impairment perturbs drug elimination processes. Drug elimination encompasses two key aspects: the fraction excreted unchanged and the fraction metabolized. The extent of a metabolized fraction can be inferred from the ratio of hepatic clearance to total body clearance. Assuming liver-based metabolism and unchanged drug excretion via urine, the equation can be restructured to elucidate this relationship.

Drugs characterized by a higher fraction of metabolized compounds are notably sensitive to changes in liver function. This sensitivity arises from their heavier reliance on metabolic pathways for elimination. As a result, hepatic impairment can substantially impact the pharmacokinetics of such drugs, potentially necessitating dosage adjustments or alternative therapeutic strategies. Vigilant monitoring of drug and metabolite concentrations is essential in managing patients with hepatic dysfunction, ensuring optimal therapeutic outcomes while minimizing adverse effects.

For many drugs, monitoring the concentrations of both the active drug and its metabolite is crucial as both contribute to the therapeutic effect.

In a patient with hepatic impairment, changes in liver function can alter drug potency. If the drug is more potent than its metabolite, liver impairment increases drug activity due to higher drug concentrations.

Conversely, if the metabolite is more potent than the drug, activity decreases due to reduced metabolite formation.

Liver impairment also affects drug elimination, which can be divided into two components: the fraction excreted unchanged and the fraction metabolized. The metabolized fraction is typically estimated from 1 - f_e.

Total body clearance can be calculated under the assumption that metabolism occurs in the liver, and the unchanged drug is excreted in the urine.

Drugs with a higher fraction of metabolized drugs are more significantly impacted by liver function changes, as they rely more on metabolism for elimination.