Excretion

• Phase I metabolites may still be quite lipid soluble and difficult to excrete
• In Phase II metabolism, Phase I metabolites are conjugated with polar endogenous molecules
• During Phase II metabolism, drugs are made more water soluble and easier to excrete
• Phase II conjugates are excreted rapidly in the urine or faeces
• Phase II reactions are anabolic reactions conjugating a hydrophilic molecule to Phase I metabolites
• All Phase II conjugates are charged to increase water solubility
• Most products of Phase II reactions are inactive
• Glucuronidation is the most common Phase II reaction
• Glucuronidation is catalysed by UGPs
• Glucuronidation involves conjugation of molecule with glucose
• Sulfation is conjugation with a sulfate group
• Paracetamol undergoes sulfation by SULTs
• SULT = sulfotransferase
• Acetylation is catalysed by NATs
• NAT = N-acetyltransferase
• Glutathione is synthesised by the liver
• Glutathione acts as a buffer to protect the liver from reactive molecules
• Glutathione has high concentration in hepatocytes
• Glutathione-S-transferases facilitate the conjugation of glutathione to reactive molecules
• Glutathione consists of glutamate, cysteine, and glycine
• Glutathione conjugation is more effective than other conjugations due to the high glutathione concentration in the liver and spontaneous reaction catalysed by enzymes
• Normal paracetamol metabolism is mainly done through Phase II reactions
• During Phase II reactions, paracetamol is mostly conjugated to sulfate and glucuronide
• Some paracetamol is excreted unchanged
• When Phase II pathways become saturated, Phase I reactions start to metabolise paracetamol
• Cyp450 metabolises paracetamol into a toxic compound that binds to cell proteins, causing cell death
• Normally, the toxic compound produced from Phase I metabolism of paracetamol is inactivated by glutathione conjugation, but its depletion occurs from saturation of Phase II reactions
• Once formed intracellularly, most drugs are highly polar
• Phase II reactions cause metabolites to be polar, meaning that they are more readily excreted but must first cross the cell membrane
• ABC-efflux transporters facilitate the removal of polar metabolites from cells
• ABC transporters exist as dimers in the membrane
• ABC transporter mechanism

  1. In the open dimer, ABC transporters accept substrate within the cell
  2. Binding of ATP causes the dimer to change shape
  3. The substrate is effluxed
  4. ATP is dephosphorylated to ADP, restoring the starting conformation
• Once a drug has undergone Phase I or Phase II metabolism, it is ready for elimination
• Transporters can direct the metabolite:

  1. Back to the systemic circulation to be eliminated in urine, or
  2. Into the bile for elimination in faeces
• Urine and faeces are major elimination pathways
• Other elimination pathways can include pulmonary, breast milk, sweat, hair and saliva
• Glomerular filtration

  • Free drug (not bound to plasma proteins) is removed at the glomerulus
  • Only small molecules will pass through the filtration slit at the glomerulus
• Active tubular secretion

  • Energy dependent process
  • Drug is transported from the blood into the urine by tubular transporter proteins
  • Molecules can compete for transport
• Tubular reabsorption

  • Passive process in which the drug in urine diffuses back into the blood
  • Favours the unionised (lipid soluble) drug, so the pH of urine is important
• If the urine is more acidic, the drug is more likely to be in its ionised form