What is first pass metabolism?

What is First-Pass Metabolism

First-pass metabolism is the process by which a drug is metabolized between its site of administration and the site where it enters the systemic circulation, resulting in reduced bioavailability of the active drug. 1

Definition and Basic Mechanism

First-pass metabolism occurs when orally administered drugs are absorbed through the gastrointestinal tract and must pass through the gut wall and liver before reaching the systemic circulation. 1 During this initial passage, drug-metabolizing enzymes break down a portion of the drug, reducing the amount of active compound that ultimately reaches target tissues. 2

The extent of first-pass metabolism directly determines a drug's oral bioavailability—the percentage of the administered dose that reaches systemic circulation unchanged. 2

Primary Sites of First-Pass Metabolism

Liver (Hepatocytes)

• The liver is the major site of first-pass metabolism for most orally administered drugs. 1
• Hepatocytes contain cytochrome P450 (CYP) enzymes responsible for metabolizing over 50% of all marketed drugs, with CYP3A4 being the predominant enzyme. 3
• Drugs with high hepatic extraction ratios (such as propranolol, morphine, lidocaine, verapamil, and nifedipine) undergo extensive first-pass metabolism, with bioavailability often below 30%. 2, 4

Intestinal Wall

• The gut wall plays an important role in first-pass metabolism, particularly for conjugation reactions (phase II metabolism). 5
• Sulphate conjugation in the intestinal mucosa is particularly significant for steroid hormones and beta-adrenoceptor stimulants. 5
• The gut wall contains metabolic enzymes that can substantially alter drug bioavailability before substances reach the liver. 3

Other Sites

• Additional potential sites include the gastrointestinal tract, blood, vascular endothelium, and lungs, though these are generally less significant. 1

Clinical Significance

Impact on Dosing

Drugs undergoing extensive first-pass metabolism require much larger oral doses compared to intravenous doses to achieve equivalent plasma concentrations. 1 For example, propranolol has an oral bioavailability of only approximately 25% due to high first-pass metabolism by the liver. 4

Route of Administration Matters

• Some drugs with extensive first-pass metabolism (such as lidocaine, naloxone, and nitroglycerin) cannot be given orally at all because too little active drug reaches systemic circulation. 1
• Intravenous administration bypasses first-pass metabolism entirely, resulting in 100% bioavailability. 1

Drugs Preferred During Special Conditions

Drugs that are inactivated by first-pass metabolism are actually preferred during lactation because even if the drug enters breast milk and is consumed by the infant, it will undergo first-pass metabolism in the infant's gut and liver, reducing systemic exposure. 2

Factors Affecting First-Pass Metabolism

Enzyme Activity

• The extent of first-pass metabolism depends heavily on the activity of drug-metabolizing enzymes in the liver and gut wall. 1
• Genetic polymorphisms (such as CYP2D6 poor metabolizers versus ultrarapid metabolizers) can dramatically alter first-pass metabolism and drug bioavailability. 2

Age-Related Changes

• Older adults experience reduced gut wall transporters and decreased first-pass metabolism, which increases oral bioavailability of drugs like diltiazem, opioids, propranolol, simvastatin, and verapamil. 2, 3
• Decreased hepatic blood flow in elderly patients (20-30% reduction) affects clearance of drugs with high hepatic extraction ratios. 2, 3

Hepatic Blood Flow

• For drugs with high hepatic extraction ratios, first-pass metabolism is primarily dependent on liver blood flow rather than enzyme activity. 2
• Conditions that reduce hepatic blood flow will decrease first-pass metabolism and increase bioavailability. 1

Plasma Protein Binding

• Only the free (unbound) fraction of a drug can undergo metabolism. 2
• Changes in protein binding can affect the extent of first-pass metabolism, though this effect may be counterbalanced by changes in clearance. 2

Mathematical Relationship

When multiple sites of first-pass metabolism exist in series (gut wall, then liver), the overall bioavailability is the product of the fraction escaping metabolism at each site. 1 This means even modest metabolism at multiple sites can result in very low overall bioavailability.

Common Pitfalls

• Do not assume oral and intravenous doses are equivalent: Drugs with significant first-pass metabolism require dose adjustments based on route of administration. 1
• Consider drug-drug interactions: CYP3A4 inhibitors or inducers can dramatically alter first-pass metabolism when given with orally administered drugs. 3
• Account for special populations: Elderly patients and those with liver disease may have altered first-pass metabolism requiring dose adjustments. 2
• Remember prodrugs: Some drugs (like codeine) require first-pass metabolism for activation; reduced first-pass metabolism decreases their efficacy rather than increasing it. 2