First Pass Metabolism (First Pass Effect)

Definition

"If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug entering the systemic circulation is decreased." - Lippincott Illustrated Reviews: Pharmacology

How It Happens - Step by Step

1. Drug is swallowed and absorbed through the intestinal wall into mesenteric capillaries
2. These drain into the portal vein, which goes directly to the liver
3. Hepatic enzymes (primarily CYP450 enzymes, especially CYP3A4) metabolize a portion of the drug
4. The gut wall also contributes (e.g., CYP3A4 and P-glycoprotein efflux)
5. Only the fraction that survives this first passage enters the hepatic vein → inferior vena cava → systemic circulation

Effect on Bioavailability

Classic Examples

Sites of First Pass Metabolism

• Gut wall - CYP3A4 and P-glycoprotein (e.g., benzylpenicillin, insulin degraded here)
• Liver - Main site; CYP450 enzymes (propranolol, lidocaine, nitroglycerin, morphine)
• Lung - For drugs given by non-GI parenteral routes; can serve as a site of first pass loss via excretion or metabolism

Routes That Bypass First Pass Metabolism

Clinical Relevance

1. Dose adjustment: Drugs with extensive first pass need much higher oral doses than IV doses (e.g., morphine oral:IV ratio is approximately 3:1)
2. Inter-patient variability: Differences in CYP450 activity, hepatic blood flow, and genetic polymorphisms cause wide variation between individuals
3. Liver disease: Cirrhosis with portosystemic shunting can dramatically increase bioavailability of high first-pass drugs (e.g., morphine, meperidine, midazolam, nifedipine oral bioavailability nearly doubles in cirrhosis - per Harrison's Principles of Internal Medicine)
4. Drug interactions: One drug can inhibit or induce the enzymes involved, affecting the first pass metabolism of another drug (e.g., grapefruit juice inhibits CYP3A4)
5. Prodrugs: Some drugs are designed to exploit first pass - they are inactive until metabolized by the liver (e.g., codeine → morphine via CYP2D6; enalapril → enalaprilat)

Summary Formula

Oral bioavailability (F) = Fraction absorbed × (1 - Extraction Ratio)

NOTE: Drug Absorption & Factors Influencing It

What is Drug Absorption?

"Absorption from the site of administration permits entry of the drug (either directly or indirectly) into plasma." - Lippincott Illustrated Reviews: Pharmacology

Mechanisms of Drug Absorption Across Membranes

Factors Influencing Drug Absorption

1. pH and Drug Ionization (pKa)

• Un-ionized form = lipid soluble → crosses membranes freely
• Ionized form = water soluble, charged → does NOT cross lipid membranes well

• Weak acids (e.g., aspirin, warfarin): better absorbed in acidic environments (stomach) where they are un-ionized
• Weak bases (e.g., morphine, codeine, atropine): better absorbed in alkaline environments (small intestine) where they are un-ionized

Ion trapping: When a drug passes into a compartment where it becomes ionized, it gets "trapped" there - it cannot diffuse back out. This is exploited clinically, e.g., alkalinizing urine to trap acidic drugs like aspirin for faster excretion in overdose.

2. Lipid Solubility

• Drugs must be lipophilic enough to dissolve in the lipid bilayer and cross membranes
• But must also have some water solubility to dissolve in GI fluids and reach the membrane surface
• Extremely hydrophilic OR extremely lipophilic drugs are both poorly absorbed
• This is why many drugs are weak acids or weak bases - they have partial lipid solubility

3. Route of Administration

4. GI Motility and Gastric Emptying

• Increased GI motility (e.g., diarrhea, metoclopramide) → faster gastric emptying → drug reaches small intestine sooner → may increase absorption rate but reduce total time for absorption
• Decreased motility (e.g., opioids, anticholinergics) → delayed gastric emptying → slower absorption onset
• Most oral absorption occurs in the small intestine (large surface area, rich vascular supply), so faster gastric emptying generally increases drug absorption

5. Blood Flow to the Absorption Site

• Greater blood flow maintains a high concentration gradient across the membrane, driving faster absorption
• IM injections absorb faster than SC because muscle has richer blood supply
• In shock states, peripheral absorption (IM, SC) is unreliable due to vasoconstriction - IV is preferred
• Sustained-release and depot preparations slow drug release to prolong absorption regardless of blood flow

6. Solubility and Drug Formulation

"Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and absorption." - Lippincott Pharmacology

• Particle size: smaller particles dissolve faster (more surface area)
• Salt form: e.g., sodium salts dissolve faster than free acid forms
• Crystal polymorphism: different crystal forms of the same drug dissolve at different rates
• Enteric coatings: protect acid-labile drugs (e.g., omeprazole) or irritating drugs (e.g., aspirin EC) - release occurs in the intestine
• Extended-release (ER/SR/XL) formulations: rate of dissolution controls rate of absorption; allows twice or once-daily dosing

7. Food and Drug Interactions

• Food can delay gastric emptying, dilute drug concentration, or chelate certain drugs (e.g., tetracyclines bind calcium in dairy)
• P-glycoprotein (P-gp): an efflux transporter in the gut wall that pumps some drugs back into the intestinal lumen, reducing absorption (e.g., digoxin). Inhibitors like verapamil increase digoxin bioavailability
• Grapefruit juice: inhibits intestinal CYP3A4 → increases absorption of many drugs (e.g., statins, calcium channel blockers)
• Antacids: raise gastric pH, altering ionization of drugs (e.g., reduces absorption of ketoconazole which needs acidic environment)

8. Drug Chemical Instability

• Some drugs are degraded before absorption:
  • Penicillin G: unstable in acidic gastric environment
  • Insulin: proteolytic enzymes in the GI tract destroy it completely - must be given by injection
  • Nitroglycerin: destroyed by hepatic first pass (>90%) if swallowed

9. Patient-Specific Factors

Summary Diagram of Key Concepts

Drug administered orally
        ↓
Dissolved in GI fluids (solubility)
        ↓
Un-ionized form (depends on pKa + pH) crosses gut wall
        ↓
P-gp efflux? CYP3A4 in gut wall? → reduced absorption
        ↓
Portal vein → LIVER → first pass metabolism
        ↓
Remaining drug → systemic circulation = BIOAVAILABILITY (F)