Chapter 2 · Module 1 of 5 · Pharmacokinetics

Absorption and Bioavailability

Physicochemical determinants, routes of administration, first-pass metabolism, and the kinetic parameters that describe how much drug reaches the systemic circulation

Passive transcellular diffusion — the dominant absorption mechanism — requires the un-ionized, lipophilic form of a drug; optimal log P is 1–3; ionized forms are membrane-impermeant; the small intestine dominates oral absorption due to its surface area; P-glycoprotein efflux limits absorption of many substrates
Routes of administration differ fundamentally in bioavailability and first-pass exposure: IV delivers 100% bioavailability with no first-pass; sublingual bypasses the liver via oral venous drainage; oral absorption traverses portal circulation to the liver before reaching systemic blood
First-pass extraction — at both the intestinal CYP3A4 and hepatic CYP enzymes — dramatically reduces oral bioavailability of high-extraction drugs; nitroglycerin and lidocaine are essentially inactive orally; cirrhosis bypasses hepatic first-pass via portosystemic shunting, dramatically increasing exposure
Absolute bioavailability (F) = AUCoral ÷ AUCIV; oral dose required = IV dose ÷ F; generic bioequivalence requires AUC and Cmax within 80–125% of the innovator; narrow therapeutic index drugs (phenytoin, cyclosporine, warfarin, levothyroxine) require level monitoring after brand-to-generic switches
Extended-release formulations lower Cmax, delay Tmax, and preserve AUC — crushing causes dose dumping with risk of fatal toxicity for opioids; enteric coating resists gastric acid, releasing drug in the duodenum; prodrug strategies exploit intestinal transporters or metabolism to improve bioavailability (valacyclovir → acyclovir)

Section 1 — Physicochemical Determinants of Absorption

Section 1

Lipophilicity, Ionization, and Molecular Size

Key Property

Lipophilicity

Log P 1–3 optimal for membrane crossing
Too hydrophilic: cannot enter lipid bilayer
Too lipophilic: trapped in membrane, not released

Key Property

Ionization (pH Partition)

Only un-ionized form crosses membranes
Ionized form is membrane-impermeant
Degree of ionization depends on drug pKa and local pH
Small intestine dominates absorption (vast surface area)

Key Property

Molecular Size and Transporters

Below ~500 daltons for efficient passive diffusion
Lipinski Rule of Five predicts poor oral absorption
P-glycoprotein (P-gp) efflux reduces absorption of substrates back into GI lumen

Section 2 — Routes of Administration

Section 2

Bioavailability, Onset, and First-Pass by Route

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 and first-pass survival

Section 3 — First-Pass Metabolism

Section 3

Pathway, High-Extraction Drugs, and Clinical Modifiers

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 to circulation

→

Systemic circulation

Bioavailable fraction (F)

Produces pharmacological effect

High-Extraction Drugs

Low Oral Bioavailability

Nitroglycerin: F ≈ 0% — sublingual or transdermal only
Lidocaine: F ≈ 0% — intravenous only
Morphine: F ≈ 30% — IV preferred for acute severe pain
Propranolol: F ≈ 25–35% — high interpatient variability

Factors Modifying First-Pass

Clinical Consequences

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 → dramatically increases bioavailability of high-extraction drugs

Section 4 — Bioavailability

Section 4

Absolute Bioavailability, Generic Substitution, and Absorption Pitfalls

Absolute Bioavailability

F = AUC_oral ÷ AUC_IV

Fraction of dose reaching systemic circulation
IV route: F = 1.0 (100%) by definition
Oral dose required = IV dose ÷ F

Generic Bioequivalence

80–125% AUC / Cmax Range

Generic must be within 80–125% of innovator AUC and Cmax
Acceptable for most drugs with wide therapeutic index
Narrow TI drugs: phenytoin, cyclosporine, tacrolimus, warfarin, levothyroxine — monitor levels after any brand switch

Factors Reducing F

Absorption Pitfalls

PPIs: reduce absorption of ketoconazole, itraconazole, atazanavir (acid-dependent dissolution)
Food fasting: reduces posaconazole, griseofulvin, ivermectin — must take with food
Roux-en-Y bypass: reduces levothyroxine and mycophenolate mofetil absorption

Section 5 — Oral Absorption Kinetics

Section 5

Cmax, Tmax, and AUC — Immediate-Release vs. Extended-Release

Immediate-release: high Cmax, early Tmax

Extended-release: lower Cmax, later Tmax, AUC equal

Minimum effective concentration (MEC)

Section 6 — Drug Formulation Effects on Absorption

Section 6

Extended-Release, Enteric Coating, and Prodrug Strategies

Extended-Release

Never Crush, Chew, or Break

Lower Cmax, later Tmax, AUC preserved vs. IR
Crushing causes dose dumping — risk of fatal toxicity with ER opioids
Abuse-deterrent formulations resist extraction and crushing
Examples: ER morphine, ER nifedipine, ER 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: PPIs
Protects gastric mucosa: enteric-coated aspirin, naproxen
Tmax 1–4 hours — unsuitable for acute pain relief

Prodrug Strategy

An inactive precursor activated by biotransformation after absorption. Valacyclovir (prodrug) → acyclovir (active): 55% oral bioavailability vs. 15–20% for acyclovir itself — the prodrug exploits intestinal amino acid transporters that the parent drug cannot access. Clopidogrel requires hepatic CYP2C19 activation; poor metabolizers have inadequate antiplatelet effect and stent thrombosis risk.

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