Pharmacokinetics — Oral Bioavailability

Oral Bioavailability

Absorption

• Drug factors
  • Most drugs absorbed from GI via passive diffusion
    • Diffusion:
      • Low molecular weight substances are readily able to permeate membranes (*see below for equation)
    • Charge
      • Charged particles display reduced permeability across phospholipid bilayers
      • pK_a → pH at which 50% of the molecules are ionized
      • Henderson-Hasselbach Equation pKa = pH + log (ionized/unionized)
      • Acids are ionized when pH > pKa
      • Bases are ionized when pH < pKa
    • Hydrophilicity
      • A degree of hydrophilicity is required for drug to cross aqueous layer immediately adjacent to enterocyte in intestinal lumen
    • Lipophilicity
      • Lipophilicity required for drug to cross phospholipid bilayer
    • Pharmaceutics
      • Dissolution of tablet/capsule
      • Enteric coating
• Patient factors
  • Rate of gastric emptying
    • Absorption surface area greater in intestines (>200m²) due to microvilli, therefore increased gastric emptying increases rate of absorption
  • Blood flow to site of absorption
  • Reverse transporters such as P-glycoprotein cause drug efflux from enterocytes, preventing absorption
  • Inflammation → increases drug absorption
  • Interaction with other co-administered drugs

Fick’s Law:

First Pass Metabolism

• Metabolism by gut bacteria (digoxin)
• Metabolism within enterocytes
• Metabolism in liver via portal circulation before reaching systemic circulation
• Secretion into bile by liver on first pass, before reaching systemic circulation

Shock

Introduction

Clinical state of acute circulatory failure with impaired oxygen utilization +/- delivery by cells leading to cellular hypoxia or dysoxia

• Hypovolaemic (Massive haemorrhage)
• Obstructive (e.g. Massive PE, tamponade)
• Cardiogenic (Acute cardiac failure)
• Distributive (Sepsis)

Effects on Bioavailability

• Drug factors will be unaltered in a patient in shock
• Patient factors
  • Gastric stasis may occur leading to decreased rate of absorption
  • Intestinal barrier – the integrity of the GI barrier may be decreased by inflammation or ischaemia and cell death, leading to greater absorption
  • Splanchnic blood flow may be decreased leading to decreased absorption
  • P-glycoprotein may be inhibited due to cell dysfunction or drug interactions (e.g. antibiotics) leading to decreased efflux → increased drug absorption
• 1^st pass metabolism
  • Concurrent treatment with antibiotics may alter the microbiota in the GI lumen, altering metabolism
  • Hepatic dysfunction may occur due to ischaemia or haemolysis
    • If hypoxia → zone 3 hepatocytes will be relatively impaired → CYP450 metabolism decreased → increased bioavailability

Sakurai 2016

Answer by Sakurai