Hepatic impairment and the dose-reduction rule

Liver impairment lowers intrinsic clearance, so a high-extraction drug's first-pass falls and its oral bioavailability rises — propranolol-like F climbs 0.25→0.77 (3.1× over-exposure) as CLint falls, while a low-extraction drug barely moves (1.09×). That is the clinical dose-reduction rule, literally F=1−E. Grade [V]; Child-Pugh anchor [L].

Hepatic impairment scales intrinsic clearance down. For a high-extraction drug E falls and F=1−E rises 25%→77% (3.1×), demanding dose reduction; a low-extraction drug is comparatively spared (1.09×). The selectivity — high-E strongly affected, low-E not — is the contrast, matching hepatic-impairment pharmacokinetics.

Less clearance, more drug

In cirrhosis the metabolic capacity of the hepatocytes falls. For a high-extraction drug — one largely removed on first pass — the oral bioavailability is F=1−E, so a drop in intrinsic clearance lowers E and raises F directly.

High-extraction drugs over-expose; low-extraction spared

Scaling intrinsic clearance down, the propranolol-like drug's bioavailability rises 0.25→0.77 — a 3.1-fold over-exposure — while a low-extraction drug rises only 1.09-fold. High-extraction drugs are defined by removal of more than ~60% on first pass (F<40% in health); in cirrhosis their F can approach 100% and they must be dosed very carefully (Clinical Pharmacokinetics, hepatic first-pass metabolism in liver disease). The direction and the high-E/low-E selectivity are reproduced [V]; the absolute exposure needs a severity→CLint calibration per agent and stays [O].