Absorption and Bioavailability

Absorption and Bioavailability - Entry Pass Granted

• Absorption: Drug entry: admin site → systemic circulation.
  • Key Routes: Oral, IV, IM, SC, Inhalational, Transdermal.
  • Cell Membranes: Lipid bilayers, drugs must cross.
• Mechanisms of Drug Transport:
  • Passive Diffusion: Down gradient, lipid-soluble, no ATP. Fick's: $J = -D \frac{dC}{dx}$.
  • Facilitated Diffusion: Carrier, no ATP, saturable.
  • Active Transport: Carrier, ATP, against gradient, saturable.
  • Endocytosis: Large drugs (Vit B12).
• Bioavailability (F): Unchanged drug fraction in systemic circulation.
  • Formula: $F = \frac{AUC_{route}}{AUC_{IV}} \times \frac{Dose_{IV}}{Dose_{route}}$
  • IV route: F = 100%.
  • Factors: First-pass metabolism, solubility, stability, pH, formulation.

⭐ High first-pass metabolism (nitroglycerin, propranolol) = low oral F; may need other routes/↑dose.

Absorption and Bioavailability - Crossing Cell Borders

Drugs cross cell membranes via several mechanisms:

• Passive Diffusion:
  • Major route; movement down concentration gradient.
  • Favors lipid-soluble, non-ionized drugs.
  • Governed by Fick's Law: $Rate \propto \frac{(C_1-C_2) \times Area \times Permeability}{Thickness}$.
  • pH & Ionization: Non-ionized drugs are more lipid-soluble, hence better absorbed. Weak acids absorb best in acidic environments (e.g., stomach); weak bases in basic environments (e.g., intestine). (📌 Unionized = Uncharged = Lipid soluble = Absorbed)
• Facilitated Diffusion:
  • Carrier-mediated transport.
  • No energy (ATP) required; follows concentration gradient.
  • Saturable, e.g., glucose transport by GLUT.
• Active Transport:
  • Carrier-mediated; requires energy (ATP hydrolysis).
  • Can move drugs against concentration gradient.
  • Saturable and site-specific.
  • E.g., P-glycoprotein (MDR1) efflux pump, Na+/K+ ATPase.
• Endocytosis & Pinocytosis:
  • Engulfment of large molecules or fluids.
  • For large drugs (e.g., Vitamin B12-intrinsic factor complex, some protein therapeutics).

⭐ P-glycoprotein (MDR1), an ATP-dependent efflux pump found in intestinal epithelium, BBB, and tumor cells, actively transports drugs out of cells. This reduces absorption of some drugs (e.g., digoxin) and contributes to multidrug resistance in cancer chemotherapy.

Absorption and Bioavailability - The Game Changers

• Absorption: Drug entry into systemic circulation from administration site.
  • Mechanisms: Passive diffusion (most common), facilitated diffusion, active transport, endocytosis/pinocytosis.
• Factors Affecting Absorption:
  • Drug-related: Lipid solubility (↑ absorption), molecular size (↓ absorption), pKa (ionization state; acidic drugs: $pH = pKa + log([A^-]/[HA])$; basic drugs: $pH = pKa + log([B]/[BH^+])$), dosage form.
  • Patient-related: Route, GI pH & motility, surface area (e.g., small intestine), blood flow, presence of food/other drugs, first-pass metabolism.
• Bioavailability (F): Fraction of administered drug reaching systemic circulation unchanged.
  • Formula: $F = \frac{AUC_{oral} \times Dose_{IV}}{AUC_{IV} \times Dose_{oral}}$
  • IV administration: 100% bioavailability (F=1).

⭐ First-pass hepatic metabolism significantly reduces oral bioavailability of drugs like lignocaine, propranolol, and nitroglycerin.

Absorption and Bioavailability - The Net Amount

Bioavailability (F) is the fraction of an administered drug that reaches systemic circulation unchanged. It quantifies the drug's absorption efficiency.

• Calculation: $F = \left( \frac{AUC_{route}}{AUC_{IV}} \right) \times \left( \frac{Dose_{IV}}{Dose_{route}} \right) \times 100%$

  • $AUC$ = Area Under the plasma concentration-time Curve, reflecting total drug exposure.
  • IV administration: F = 100% (by definition).
  • Oral F: Often < 100% due to incomplete absorption and first-pass metabolism.

• First-Pass Metabolism:

  • Pre-systemic drug metabolism, primarily in the liver and gut wall.
  • Significantly reduces F of orally administered drugs like Nitroglycerin, Propranolol, Lignocaine.
  • Drugs with high extraction ratio (ER > 0.7) have low oral bioavailability.

• Factors Influencing Bioavailability:

  • Drug properties: solubility, pKa, formulation (e.g., salt form, particle size).
  • Patient factors: GI pH, gastric emptying, intestinal motility, food interactions, hepatic function, disease states (e.g., malabsorption).

for IV and oral drug administration illustrating bioavailability differences)

⭐ For drugs with high first-pass metabolism (e.g., Lignocaine, Nitroglycerin), oral doses must be considerably higher than IV doses to achieve equivalent therapeutic plasma concentrations due to reduced bioavailability.

High‑Yield Points - ⚡ Biggest Takeaways

• Absorption: Drug entry into systemic circulation from administration site.
• Bioavailability (F): Fraction of unchanged drug reaching systemic circulation; 100% for IV.
• First-pass metabolism (liver/gut): Markedly ↓ oral bioavailability (e.g., nitroglycerin, lignocaine).
• Key factors: Lipid solubility, pKa (drug ionization), pH, surface area.
• Weak acids best absorbed in acidic pH; weak bases in alkaline pH.
• P-glycoprotein (MDR1): Efflux transporter in gut, ↓ absorption.
• AUC (Area Under Curve) quantifies bioavailability and extent of absorption.