Absorption and Distribution

• Many potential drug candidates emerge from in vitro testing, but this does not necessarily mean that they will be useful
• Many potential drug candidates emerge from in vitro testing, but this does not necessarily mean that they will be useful

  
• Useful drugs also have to be sufficiently stable in vivo so that effective concentrations are achieved and maintained
• Understanding the processes that influence drug disposition in vivo is critical to understanding drug action
• A = absorption

  D = distribution

  M = metabolism

  E = elimination
• Oral Drug Absorption

  1. The drug in the intestine is absorbed into the portal circulation via mesenteric vessels
  2. Portal blood is first delivered to the liver via the portal vein
  3. The liver is the major organ of biotransformation
  4. The metabolised drug is sent to the heart via the inferior vena cava
• The abdominal aorta branches into the hepatic artery which provides oxygen to the liver
• The abdominal aorta branches into the hepatic artery which provides oxygen to the liver
• After oral absorption, the drug concentration builds up in serum but the body also acts on the drug to convert it into readily eliminated forms
• After oral absorption, the drug concentration builds up in serum but the body also acts on the drug to convert it into readily eliminated forms
• Elimination begins from the time the drug is orally administered
• Elimination begins from the time the drug is orally administered
• Passive diffusion through membranes is an important mechanism of drug absorption in the enzyme

  
• Simple diffusion through membranes of the small intestine is governed by the permeability of the membrane and the concentration gradient
• Fick's Law:

  Flux (across membrane) = P*A (C1 - C2)

  
• C1 = concentration in the intestinal lumen

  C2 = concentration in the body

  A = surface area of the membrane

  P = permeability coefficient
• The permeability coefficient indicates mobility of the drug in the lipid membrane
• SLC Influx Transporters = solute carrier transporters
• SLC influx transporters transport ions across the membranes
• SLC influx transporters generally increase the intestinal uptake of numerous drugs
• OATs and OATPs are major classes of SLC transporters for anions
• OCTs and OCTNs are major classes of SLC transporters for cations
• Not all SLC transporters require ATP
• SLCs can be secondary active transporters, meaning that they utilise a concentration gradient that was established actively
• ABC efflux transporters in enterocytes decrease drug uptake into the portal circulation
• Efflux transporters transport the drug from the enterocyte back into the intestinal lumen
• P-glycoprotein is the most studied ABC efflux transporter
• When P-glycoprotein is present, the plasma [drug] is much lower than when the transporter isn't present
• Ionisation influences drug movement between aqueous and lipid environments
• Strong acids and bases are ionised at any pH
• For weak acids and bases, the extent of ionisation depends on the pH of the aqueous environment
• Henderson-Hasselbach equation

  • Describes the ratio between concentrations of an unprotonated acid/base and its conjugate form in relation to the pH of the environment
• For a weak base, pKb = 14 - pKa
• Note that when pH is the same as pKa, the concentration of protonated and deprotonated acid/base is the same
• pH varies for different biological fluids
• The stomach is acidic
• The urine varies in acidity dependent on the diet
• The small intestine is basic
• the small intestine will do most absorption even if it can occur in the stomach due to the higher surface area
• pH also affects excretion in the kidney due to the diffusion through renal membranes