Chapter 2 · Module 1 · Visual Summary
Absorption and Bioavailability
Physicochemical determinants, routes, first-pass metabolism, and kinetic parameters
Physicochemical Determinants of Absorption
Key Property
Lipophilicity
- Log P 1–3 optimal for membrane crossing
- Too hydrophilic: cannot enter lipid bilayer
- Too lipophilic: trapped in membrane
Key Property
Ionization (pH Partition)
- Un-ionized form crosses membranes
- Ionized form is membrane-impermeant
- Small intestine dominates absorption (surface area)
Key Property
Molecular Size
- Below ~500 daltons for passive diffusion
- Lipinski Rule of Five predicts poor oral absorption
- P-glycoprotein efflux reduces absorption of substrates
Routes of Administration — Comparison
| Route |
Bioavailability |
Onset |
First-Pass |
Key Clinical Use |
| Intravenous |
100% |
Seconds |
None |
Emergencies, drugs with zero oral bioavailability |
| Sublingual |
High (drug-specific) |
1–2 min |
None |
Nitroglycerin, buprenorphine |
| Transdermal |
Drug-specific |
12–24 hr |
None |
Fentanyl, nicotine, estradiol patches |
| Intramuscular |
Near-complete |
10–30 min |
None |
Vaccines, depot antipsychotics |
| Subcutaneous |
Near-complete |
Slower than IM |
None |
Insulin, biologics, low-molecular-weight heparins |
| Oral |
Variable (F = 0–1) |
15–60 min |
Yes (portal → liver) |
Most chronic therapy; requires absorption + first-pass survival |
First-Pass Metabolism — Pathway and Consequences
Ingestion
Oral dose
Drug dissolved in GI tract
→
Intestinal epithelium
Absorbed fraction
CYP3A4 in enterocytes removes some drug
→
Liver (first pass)
Hepatic extraction
CYP enzymes metabolize drug; only fraction escapes
→
Systemic circulation
Bioavailable fraction (F)
Produces pharmacological effect
High-Extraction Drugs
Low oral bioavailability
- Nitroglycerin: F ≈ 0% — sublingual only
- Lidocaine: F ≈ 0% — intravenous only
- Morphine: F ≈ 30% — intravenous preferred for acute use
- Propranolol: F ≈ 25–35% — high inter-patient variability
Factors Increasing First-Pass
Reduced oral bioavailability
- Grapefruit: irreversibly inhibits intestinal CYP3A4 for 24–72 hours — increases exposure of substrates
- Rifampin: induces CYP3A4 — reduces bioavailability of substrates
- Cirrhosis: portosystemic shunting bypasses liver — increases bioavailability of high-extraction drugs
Bioavailability (F) — Definition and Clinical Application
Absolute Bioavailability
F = AUCoral / AUCIV
- Fraction of dose reaching systemic circulation
- Intravenous route: F = 1.0 (100%) by definition
- Oral dose needed = intravenous dose ÷ F
Generic Bioequivalence
80–125% AUC / Cmax range
- Generic must be within 80–125% of innovator AUC and Cmax
- Acceptable for most drugs
- Narrow therapeutic index: phenytoin, cyclosporine, tacrolimus, warfarin, levothyroxine — monitor levels after switch
Factors Reducing F
Bioavailability pitfalls
- Proton pump inhibitors: reduce absorption of ketoconazole, itraconazole, atazanavir
- Food fasting: reduces posaconazole, griseofulvin, ivermectin (must take with food)
- Roux-en-Y bypass: levothyroxine, mycophenolate mofetil reduced
Oral Absorption Kinetics — Cmax, Tmax, and Area Under the Curve
Immediate-release: high Cmax, early Tmax
Extended-release: lower Cmax, later Tmax, AUC equal
Minimum effective concentration (MEC)
Drug Formulation Effects on Absorption Profile
Extended-Release
Never crush, chew, or break
- Lower Cmax, later Tmax, AUC preserved
- Crushing causes dose dumping — risk of fatal toxicity with opioids
- Abuse-deterrent formulations resist extraction
- Examples: extended-release morphine, extended-release nifedipine, extended-release phenytoin
Enteric Coating
pH-dependent release in duodenum
- Intact in stomach (pH 1–3), dissolves in duodenum (pH 5.5–6.8)
- Protects acid-labile drugs: proton pump inhibitors
- Protects gastric mucosa: enteric-coated aspirin, naproxen
- Tmax 1–4 hours — unsuitable for acute pain relief
Prodrug concept: An inactive precursor activated by biotransformation after absorption. Valacyclovir (prodrug) → acyclovir (active): 55% oral bioavailability vs. 15–20% for acyclovir itself, because the prodrug exploits intestinal amino acid transporters. Clopidogrel requires hepatic cytochrome P450 2C19 activation — poor metabolizers have inadequate antiplatelet effect.