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Drug Absorption and Distribution - Complete Guide

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Overview: The ADME Framework

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PART 1: DRUG ABSORPTION

Definition

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Routes of Administration

Key clinical point: IV administration gives 100% bioavailability by definition, and is the reference standard against which all other routes are compared.

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Mechanisms of GI Absorption

1. Passive Diffusion

• The most common mechanism for most drugs
• Driven by concentration gradient (high → low)
• No carrier protein needed; not saturable; low structural specificity
• Water-soluble drugs pass through aqueous channels/pores
• Lipid-soluble drugs dissolve directly through the lipid bilayer

2. Facilitated Diffusion

• Uses specialized transmembrane carrier proteins
• No energy required; moves drug down its concentration gradient
• Can be saturated and competitively inhibited
• Used for large molecules that cannot passively diffuse

3. Active Transport

• Carrier-protein mediated, energy-dependent (ATP hydrolysis)
• Can move drugs against a concentration gradient
• Saturable and selectively inhibited
• Example: levodopa is actively transported into the brain

4. Endocytosis

• Used for very large molecules (e.g., Vitamin B12)
• Cell membrane engulfs the drug, forms an intracellular vesicle
• Exocytosis is the reverse - used to secrete substances (e.g., norepinephrine from nerve terminals)

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Factors Influencing Absorption

A. pH and Ionization (Henderson-Hasselbalch)

• Weak acid (HA): HA ⇌ H⁺ + A⁻ → the uncharged form HA crosses membranes
• Weak base (BH⁺): BH⁺ ⇌ B + H⁺ → the uncharged form B crosses membranes

• Weak acids (aspirin, pKa ~3.5) are better absorbed in the acidic stomach where they remain mostly non-ionized
• Weak bases (morphine, pKa ~8) are better absorbed in the alkaline small intestine
• Ion trapping: A charged drug becomes "trapped" on the side of the membrane where it ionizes - e.g., basic drugs accumulate in acidic urine

B. Drug Solubility

• Very hydrophilic drugs: poor absorption due to inability to cross lipid membranes
• Very lipophilic drugs: also poor absorption due to insolubility in aqueous fluids at cell surfaces
• Ideal drugs: largely lipophilic but with some aqueous solubility - this is why many drugs are weak acids or weak bases

C. Chemical Instability

• Penicillin G: destroyed by gastric acid (low pH)
• Insulin: destroyed by GI proteolytic enzymes
• Such drugs require non-oral routes

D. Drug Formulation

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Bioavailability

• IV administration = 100% bioavailability by definition
• Measured by comparing the Area Under the Curve (AUC) of oral vs. IV administration

F = AUC(oral) / AUC(IV) × 100%

First-Pass Hepatic Metabolism

• Nitroglycerin: >90% cleared on first pass → given sublingually, transdermally, or IV
• Lidocaine: extensive first-pass → not given orally
• Morphine: ~33% oral bioavailability due to first-pass

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PART 2: DRUG DISTRIBUTION

Definition

• Which tissues the drug reaches
• The concentration at the site of action
• Duration of drug effect

1. Cardiac output and local blood flow
2. Capillary permeability
3. Tissue volume
4. Protein binding (plasma and tissue)
5. Lipophilicity of the drug

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A. Blood Flow

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B. Capillary Permeability and the Blood-Brain Barrier (BBB)

• Liver/spleen capillaries: Large fenestrations with slit junctions → even large plasma proteins can pass through
• Brain capillaries (BBB): Continuous endothelium with tight junctions and astrocyte foot processes → no slit junctions

• ✅ Lipid-soluble drugs (dissolve through endothelial cell membranes)
• ✅ Carrier-transported drugs (e.g., levodopa via large neutral amino acid transporter)
• ❌ Ionized/polar drugs
• ❌ Large-molecule drugs

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C. Plasma Protein Binding

• Albumin - binds most acidic drugs (warfarin, NSAIDs, penicillin) and some basic drugs
• Alpha-1-acid glycoprotein (AAG) - binds basic drugs (lidocaine, propranolol)
• Globulins - bind thyroid hormones, steroid hormones

Key Principles:

1. Only free (unbound) drug is pharmacologically active - bound drug cannot reach receptors, be metabolized, or be excreted
2. Protein binding acts as a drug reservoir - bound drug dissociates as free drug is eliminated
3. Binding is reversible and typically in equilibrium
4. Binding is saturable at high drug concentrations

Drug Displacement Interactions:

Effect of Disease on Protein Binding:

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D. Volume of Distribution (Vd)

Vd = Total amount of drug in body / Plasma concentration

The Three Body Water Compartments:

Interpreting Vd:

• Small Vd (3-5 L): Drug stays in plasma - likely large or highly protein-bound (e.g., heparin, warfarin)
• Moderate Vd (10-20 L): Distributes into extracellular fluid (e.g., gentamicin)
• Large Vd (>42 L): Extensively tissue-distributed - may be hard to remove by dialysis (e.g., digoxin, tricyclic antidepressants)

Clinical Importance of Vd:

Loading dose = Vd × Target plasma concentration

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E. Tissue Binding and Sequestration

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F. Special Populations and Distribution

Neonates:

• Higher total body water (70-85% vs. 50-60% in adults) → higher Vd for water-soluble drugs (e.g., aminoglycosides need higher mg/kg dose)
• Very little body fat (~1-15% vs. 20%+ in adults) → less accumulation of lipophilic drugs
• Reduced plasma protein binding → higher free drug concentrations at the same total plasma level → increased risk of toxicity
• BBB is more permeable → drugs like bilirubin and morphine reach CNS more readily

Elderly:

• Decreased plasma albumin → higher free fractions of acidic drugs
• Decreased body water → higher concentration of water-soluble drugs
• Increased fat → larger Vd for lipophilic drugs → prolonged effect

Hepatic failure:

• Decreased albumin synthesis → more free drug
• Decreased first-pass metabolism → higher bioavailability of oral drugs

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Summary: Absorption vs. Distribution

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Quick-Reference: Key Drug Examples

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