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1st pass metabolism

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First-Pass Metabolism (Presystemic Elimination)

Definition

First-pass metabolism (also called presystemic elimination or presystemic extraction) is the biotransformation of an orally administered drug in the intestinal wall and/or liver before it reaches the systemic circulation, thereby reducing the amount of active drug available to the body.
First-pass metabolism: oral drugs pass through the portal circulation and liver before reaching systemic circulation, while IV drugs bypass this entirely
Figure: Oral drugs are exposed to the liver via portal circulation and may be extensively metabolized before reaching systemic circulation. IV drugs bypass this entirely. - Lippincott Illustrated Reviews: Pharmacology

Pathway of First-Pass Metabolism

After oral ingestion, the drug follows this sequence:
  1. GI lumen - drug is absorbed across the intestinal epithelium (enterocyte)
  2. Enterocyte - may undergo metabolism by CYP3A4 in the gut wall, or be pumped back into the lumen by P-glycoprotein (efflux transporter)
  3. Portal vein - absorbed drug enters the portal venous system
  4. Liver (hepatocyte) - drug may be metabolized by CYP450 enzymes (especially CYP3A4, CYP2D6) or excreted into bile via biliary canaliculi
  5. Systemic circulation - only the fraction that survives all these steps reaches the bloodstream
Mechanism of presystemic elimination showing drug absorption through enterocytes into portal vein, then hepatic metabolism and biliary excretion. P-glycoprotein and other transporters are shown
Figure: Presystemic elimination mechanisms - Harrison's Principles of Internal Medicine 22E

Effect on Bioavailability

Bioavailability (F) is the fraction of an administered dose that reaches systemic circulation unchanged. First-pass metabolism is a major reason why oral bioavailability is less than 100%.
Bioavailability (F) = AUC(oral) / AUC(IV) × 100%
The higher the hepatic extraction ratio, the greater the first-pass effect, and the lower the oral bioavailability. For high-extraction drugs, hepatic clearance approaches hepatic blood flow - these drugs have very low oral bioavailability. - Tietz Textbook of Laboratory Medicine

Classic Examples of High First-Pass Drugs

DrugFirst-Pass EffectClinical Implication
Nitroglycerin>90% clearedCannot be given orally; use sublingual/transdermal/IV
LidocaineExtensiveNot used as oral agent
NaloxoneExtensiveIV/intranasal route required
MorphineSignificantOral dose much higher than IV dose
PropranololLargeHigh oral dose given to account for first-pass loss
Midazolam>50%Bioavailability <50% orally
AsenapineExtensive if swallowedFormulated as sublingual tablet

Routes That Bypass First-Pass Metabolism

RouteMechanism of Bypass
SublingualAbsorbed directly into systemic (not portal) veins
TransdermalAbsorbed into systemic veins, bypasses portal circulation
IV/IM/SubcutaneousDirectly enters systemic circulation
InhalationBypasses hepatic first pass (but lungs may contribute minor metabolism)
Rectal (lower rectum)Inferior vena cava drainage; ~50% bypass (upper rectal veins drain to portal system)
  • Katzung's Basic and Clinical Pharmacology, 16th Edition

Factors Affecting Extent of First-Pass Metabolism

  1. Hepatic blood flow - reduced flow (e.g., in cirrhosis, congestive heart failure, portal hypertension) decreases first-pass extraction, raising systemic drug levels and increasing toxicity risk for high-extraction drugs
  2. Enzyme induction/inhibition - CYP450 inducers (rifampin, phenytoin) increase first-pass and reduce bioavailability; inhibitors (ketoconazole, grapefruit) reduce first-pass and raise bioavailability
  3. Genetic polymorphisms - CYP2D6 poor metabolizers vs. ultra-rapid metabolizers show dramatically different first-pass effects (e.g., codeine toxicity in ultra-rapid metabolizers)
  4. Gut wall transporters - P-glycoprotein efflux in enterocytes reduces absorption before the drug even reaches the liver
  5. Age and disease - liver disease reduces first-pass effect; elderly may have reduced hepatic mass and blood flow

Clinical Significance

  • Drugs with high first-pass metabolism have high oral-to-parenteral dose ratios (e.g., morphine oral dose ~3x the IV dose)
  • Liver disease can dramatically increase systemic exposure to high-extraction drugs - dose reduction is required
  • Drug interactions at CYP3A4 or P-glycoprotein level can unpredictably alter bioavailability of high-first-pass drugs
  • Pro-drugs can exploit first-pass metabolism: codeine is converted to morphine in the liver by CYP2D6, making it an active analgesic only after first-pass conversion
Sources: Lippincott Illustrated Reviews: Pharmacology | Goodman & Gilman's Pharmacological Basis of Therapeutics | Harrison's Principles of Internal Medicine 22E | Katzung's Basic and Clinical Pharmacology 16E | Tietz Textbook of Laboratory Medicine 7E
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