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USMLE Step 1Pharmacology: principles and autonomic drugsEP 04 of 16

First-pass metabolism and bioavailability: calculating oral F from AUC

A swallowed drug passes through the gut wall and liver before it reaches the circulation. Learn how first-pass metabolism lowers bioavailability and how to calculate oral F from AUC and dose.

  • 5:18 video
  • 3 min read
  • 8 sources
  • Published 15 Nov 2026
Video lesson · 5:18 · Watch on YouTubeSeries: Pharmacology: Pharmacokinetics & Autonomic Drugs · @medservatory
Chapters (11)
By the end of this lesson

Explain hepatic first-pass metabolism and calculate oral bioavailability from AUC data.

The short version

  1. First-pass metabolism is removal of drug by the gut wall and liver before it reaches the systemic circulation; high first-pass drugs have a low oral F.
  2. Bioavailability (F) is the fraction of a dose that reaches the systemic circulation as intact drug, and for an intravenous dose it is 100% by definition.
  3. F = fraction absorbed × fraction that escapes first-pass removal.
  4. F is the dose-corrected oral AUC divided by the dose-corrected intravenous AUC.
  5. Routes that bypass the portal vein, such as intravenous, sublingual and transdermal, skip the first pass.

Same drug, different route: why first-pass metabolism matters

A nitroglycerin tablet, swallowed, loses a large share of its drug on the way to the bloodstream. The same tablet, held under the tongue, does not.[4][5]

The drug is the same and only the route differs. This lesson explains first-pass metabolism and bioavailability, and shows how to calculate oral bioavailability from AUC (area under the plasma concentration–time curve) data.

What bioavailability (F) means

Bioavailability, called F, is the fraction of a dose that reaches the systemic circulation as intact drug.[1][6]

An intravenous dose goes straight into the blood, so its bioavailability is, by definition, 100%. Other routes are compared with it.[2][6][7]

Because F is the fraction that reaches the circulation, the amount that arrives is the dose multiplied by F. A drug with a low F therefore needs a larger dose by that route to deliver the same amount to the blood.[5]

First-pass metabolism and the hepatic extraction ratio

Follow a swallowed tablet. It dissolves, crosses the gut wall and enters the portal vein. Portal blood goes to the liver before it goes anywhere else. That first trip is the first pass: the gut wall and the liver can remove drug before it ever reaches the systemic circulation.[1][5]

How much the liver removes depends on the hepatic extraction ratio, the fraction it takes out in one pass. A fully absorbed drug with a hepatic extraction ratio of 0.8 leaves only about 20% to enter the circulation.[5][6]

Oral bioavailability
F = fraction absorbed × fraction escaping first-pass removal

With full absorption and an extraction ratio of 0.8, the fraction escaping is 1 − 0.8 = 0.2, so F ≈ 0.2. A teaching simplification: gut-wall loss is not separated out.

Nitroglycerin, propranolol, morphine, lidocaine and verapamil are classic high first-pass drugs. Because F is low for them, a high first-pass drug needs a much larger oral than intravenous dose.[5][8]

Routes that bypass first-pass metabolism

Routes that skip the portal vein skip the first pass.[4][8]

Routes that skip the first pass
RouteWhy it skips the first pass
IntravenousEnters the systemic circulation directly
SublingualThe tongue drains to the superior vena cava, not the portal vein
TransdermalDoes not pass through the portal circulation

This is why the nitroglycerin tablet in the opening behaves differently under the tongue: venous blood from the tongue drains to the superior vena cava, so the drug reaches the systemic circulation without a trip through the liver.[4][8]

Calculating oral bioavailability from AUC

To measure it, give the drug intravenously and by mouth, and plot plasma concentration against time. The area under each curve, the AUC, is proportional to the amount of drug that reached the circulation, provided clearance is the same both times.[1][6][7]

When the doses are equal, the doses cancel and F is the oral AUC divided by the intravenous AUC. If the doses differ, correct for them: divide the oral AUC by the oral dose, divide the intravenous AUC by the intravenous dose, and then divide the first result by the second.[6][7]

Absolute oral bioavailability
F = (AUC oral / dose oral) ÷ (AUC IV / dose IV)

With equal doses this reduces to F = AUC oral ÷ AUC IV.

Worked example with equal doses (synthetic numbers)
  1. IV 100 mg gives an AUC of 50 mg·h/L; oral 100 mg gives an AUC of 20 mg·h/L
  2. F = 20 / 50 = 0.4, so 40% bioavailable
Worked example with different doses
  1. Oral 250 mg gives an AUC of 50 mg·h/L; IV 100 mg gives an AUC of 50 mg·h/L
  2. Oral: 50 / 250 = 0.2
  3. IV: 50 / 100 = 0.5
  4. F = 0.2 / 0.5 = 0.4, still 40%

The rest was lost to incomplete absorption and first-pass metabolism.

What changes first-pass removal

Anything that changes first-pass removal changes F. An enzyme inhibitor raises it, and so does a portosystemic shunt, which lets portal blood bypass the liver.[5][6]

In both cases less drug is removed on the first pass, so more of the absorbed dose escapes to the circulation and F rises.[5][6]

Practice question

Original · USMLE style
Your turnQB-MS-S1-PHARM-002-01

A healthy volunteer takes part in a pharmacokinetic study of drug Z. On one day he receives 15 mg intravenously, and the area under the plasma concentration-time curve (AUC) is 30 mg·h/L. A week later he receives 150 mg orally, and the AUC is 90 mg·h/L.

What is the oral bioavailability of drug Z?
Pick one option. Your answers stay on this device.

Common questions

What is first-pass metabolism?

It is the removal of drug by the gut wall and liver before it reaches the systemic circulation. Orally absorbed drug crosses the gut wall and enters the portal vein, so it reaches the liver first.

How do you calculate oral bioavailability from AUC?

F = (AUC oral / dose oral) ÷ (AUC IV / dose IV). With equal doses, F is simply the oral AUC divided by the intravenous AUC.

Which routes bypass first-pass metabolism?

Intravenous, sublingual and transdermal routes skip the portal vein. Venous blood from the tongue drains to the superior vena cava, not the portal vein.

Which drugs have high first-pass metabolism?

Nitroglycerin, propranolol, morphine, lidocaine and verapamil are classic high first-pass drugs, so their oral bioavailability is low.

Transcript

Read the full narration, by chapter622 words

0:00The puzzle: same drug, different route

A nitroglycerin tablet, swallowed, loses a large share of its drug on the way to the bloodstream. The same tablet, held under the tongue, does not. Same drug, different route. Why does the route change how much arrives? Today: explain first-pass metabolism, and calculate oral bioavailability from AUC data.

0:22Bioavailability and the intravenous reference

Bioavailability, called F, is the fraction of a dose that reaches the systemic circulation as intact drug. An intravenous dose goes straight into the blood, so its bioavailability is, by definition, 100%.

0:37The swallowed route: gut wall, portal vein, liver

Follow a swallowed tablet. It dissolves, crosses the gut wall, and enters the portal vein. Portal blood goes to the liver before it goes anywhere else. That first trip is the first pass: the gut wall and the liver can remove drug before it ever reaches the systemic circulation. How much the liver removes depends on the

0:57Extraction ratio and high first-pass drugs

hepatic extraction ratio, the fraction it takes out in one pass. A fully absorbed drug with a hepatic extraction ratio of 0.8 leaves only about 20% to enter the circulation. So bioavailability is the fraction absorbed, times the fraction that escapes first-pass removal. Nitroglycerin, propranolol, morphine, lidocaine and verapamil are classic high first-pass drugs.

1:26Routes that bypass first pass

Routes that skip the portal vein skip the first pass: intravenous, transdermal, and sublingual, because the tongue drains to the superior vena cava. So a high first-pass drug needs a much larger oral than intravenous dose.

1:42AUC and the bioavailability formula

Now measure it. Give the drug intravenously and by mouth, and plot plasma concentration against time. The area under each curve, the AUC, is proportional to the amount of drug that reached the circulation, provided clearance is the same both times. With equal doses, F is the oral AUC divided by the intravenous AUC. If the doses differ, correct for them: F is the oral AUC over the oral dose, divided by the intravenous AUC over the intravenous dose.

2:18Worked example (synthetic numbers)

An intravenous dose of 100 milligrams gives an AUC of 50. An oral dose of 100 milligrams gives 20. Twenty over 50 is 0.4: 40% bioavailable. Now an oral dose of 250 milligrams, with an AUC of 50. Fifty over 250 is 0.2. Fifty over 100 is 0.5. 0.2 over 0.5 is still 0.4. The rest was lost to incomplete absorption and first-pass metabolism.

2:56Enzyme inhibitors and portosystemic shunts

Anything that changes first-pass removal changes F. An enzyme inhibitor raises it, and so does a portosystemic shunt, which lets portal blood bypass the liver.

3:08Practice question

Your turn. A healthy volunteer takes part in a pharmacokinetic study of drug Z. On 1 day he receives 15 milligrams intravenously, with an AUC of 30 milligram-hours per litre. A week later he receives 150 milligrams orally, with an AUC of 90. What is the oral bioavailability of drug Z? A, 10%. B, 30%. C, 60%. D, 120%. E, 300%. Pause here and decide.

3:49Explanation: working through the options

A is out: 10% is only the ratio of the doses, 15 over 150, and ignores the AUCs. C is out: 60% is the oral AUC over the oral dose, 90 over 150, forgetting the intravenous arm. D is out: 120% multiplies the two ratios where you should divide, and oral bioavailability cannot exceed 100%. E is out: 300% is the raw AUC ratio, 90 over 30, with no dose correction, and it exceeds 100%. So the answer is B. Oral: 90 over 150 is 0.6. Intravenous: 30 over 15 is two. 0.6 over two is 0.3: 30%. Three things to keep.

4:45High-yield recap and next lesson

One: first pass is removal by the gut wall and liver before the circulation; high first-pass drugs have a low oral F. Two: F is the dose-corrected oral AUC over the intravenous AUC, and intravenous is 100%. Three: routes that bypass the portal vein, such as intravenous, sublingual and transdermal, skip the first pass. Next, the volume of distribution.

Sources

Numbers in the text, e.g. [1], point here
  1. MSD Manual Professional Version. Drug Bioavailability. msdmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-bioavailability
  2. MSD Manual Professional Version. Drug Absorption. msdmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-absorption
  3. MSD Manual Professional Version. Drug Metabolism. msdmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-metabolism
  4. Deranged Physiology. Routes of administration. derangedphysiology.com/main/cicm-primary-exam/pharmacokinetics/Chapter-112/routes-administration
  5. Deranged Physiology. Hepatic clearance. derangedphysiology.com/main/cicm-primary-exam/pharmacokinetics/Chapter-3336/hepatic-clearance
  6. Deranged Physiology. Bioavailability and bioequivalence. derangedphysiology.com/main/cicm-primary-exam/pharmacokinetics/Chapter-121/bioavailability-and-bioequivalence
  7. Wikipedia. Bioavailability (secondary source, used for the formula). en.wikipedia.org/wiki/Bioavailability
  8. Europe PMC supporting articles: europepmc.org/article/PMC/PMC13582386 · europepmc.org/article/PMC/PMC11052794 · europepmc.org/article/PMC/PMC11954733 · europepmc.org/article/PMC/PMC12389210 · europepmc.org/article/PMC/PMC13371791 · europepmc.org/article/PMC/PMC13743574

The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.

Image credits. Illustrations: Servier Medical Art (smart.servier.com), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/); adapted (recoloured, outlined, resized): intestinal villi, liver, liver lobule, tongue, patch. Drug tablet icon: drug-tablet-1 by Servier (via bioicons.com), CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/); adapted (rasterised, recoloured, outlined). Digestive tract: NIAID NIH BioArt Source (bioart.niaid.nih.gov), public domain. All other diagrams are original (schematic curves; the numbers are synthetic teaching values).

Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-PHARM-002.

For exam study only, not medical advice. Read the medical disclaimer.

In this series

Playlist on YouTube
← Previous · EP 03Therapeutic index explained: TD50 / ED50
  1. EP 01Potency vs efficacy: EC50, Emax and agonist types5:17
  2. EP 02Competitive vs noncompetitive antagonists: effect on EC50 and Emax5:01
  3. EP 03Therapeutic index explained: TD50 / ED505:01
  4. EP 04First-pass metabolism and bioavailability: calculating oral F from AUC5:18
  5. EP 05Volume of distribution: why Vd can be bigger than the body5:17
  6. EP 06Clearance and half-life: t½ = 0.693 × Vd / CL5:01
  7. EP 07Zero-order vs first-order elimination explained5:12
  8. EP 08Loading dose and maintenance dose, explained5:02
  9. EP 09CYP450 inducers and inhibitors: how they change drug levels5:16
  10. EP 10Autonomic receptors: alpha, beta and muscarinic5:33
  11. EP 11Beta blocker selectivity: beta-1, ISA and alpha blockade5:24
  12. EP 12Vasopressors compared: receptors, pressure and heart rate5:46
  13. EP 13Organophosphate poisoning: muscarinic vs nicotinic signs5:36
  14. EP 14Receptor desensitization, downregulation and upregulation5:01
  15. EP 15Beta-lactams and vancomycin: enzyme versus substrate5:04
  16. EP 16Protein synthesis inhibitors: 30S vs 50S antibiotics5:07