PharmacologyTier 1Medical Sciences concept

Hepatic extraction ratio and first-pass metabolism - effect on bioavailability

Core concept

Extraction ratio (E) = fraction of drug removed in a single pass through the liver

```

E = (C-in - C-out) / C-in

Hepatic clearance CL-H = Q-H x E (Q-H = hepatic blood flow, ~1.5 L/min)

Oral bioavailability F = f-abs x (1 - E)

```

	High extraction (E > 0.7)	Low extraction (E < 0.3)
CL determined by	Hepatic blood flow - "flow-limited"	Intrinsic clearance and free fraction - "capacity-limited"
Oral F	Low (large first pass)	High
Sensitive to	Cardiac output, cirrhosis, portosystemic shunting, propranolol/food	Enzyme induction/inhibition, protein binding, hepatocellular function
Examples	Propranolol, metoprolol, morphine, GTN, lidocaine, verapamil, TCAs, midazolam	Warfarin, phenytoin, diazepam, theophylline, paracetamol

High-extraction drugs show huge oral-to-IV dose differences
- Propranolol F ~25-30%, morphine F ~30%, GTN F near 0 (hence sublingual and transdermal only)
- The oral dose is many times the IV dose - a swapped route is a serious error
Enzyme inhibition or induction barely changes clearance of a high-extraction drug (already limited by flow) but markedly changes its bioavailability
- -> the interaction manifests as a jump in oral exposure, not in IV
Protein binding matters only for low-extraction drugs
- Displacement raises free fraction transiently but clearance rises too -> new steady-state free concentration is usually unchanged
- This is why "protein binding displacement interactions" are largely a teaching myth, with phenytoin the practical exception through altered level interpretation
Cirrhosis attacks both regimes, by different routes
- Portosystemic shunting bypasses the liver -> F of high-extraction drugs rises sharply (propranolol, morphine, midazolam)
- dec functioning hepatocytes -> dec intrinsic clearance of low-extraction drugs
- dec albumin -> inc free fraction; phase I (CYP) is affected before phase II (glucuronidation)
Routes that bypass first pass: IV, sublingual, buccal, transdermal, inhaled, rectal (partially), intranasal

IV-to-oral switches must use published conversion ratios, not the same number
- Morphine IV : oral = 1 : 3; metoprolol IV to oral roughly 1 : 2.5
Cirrhosis - halve or avoid high-extraction sedatives and opioids; a standard dose of oral morphine or midazolam can precipitate encephalopathy
- Use LOT benzodiazepines (lorazepam, oxazepam, temazepam) which need only glucuronidation
Heart failure and shock reduce hepatic blood flow -> dec clearance of flow-limited drugs (lidocaine toxicity in cardiogenic shock is the classic)
Beta-blockade itself reduces hepatic blood flow -> propranolol reduces the clearance of lidocaine and of itself
Food transiently raises splanchnic flow -> inc F of some high-extraction drugs (propranolol)
There is no validated "Child-Pugh dose adjustment" equivalent to eGFR-based renal dosing - the principle above is what you reason from

3 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.