Lecture 8 - Drug metabolism and elimination (the kidneys)

• Glomerular filtration


  1. Glomerulus filters substances from the blood into the capsule and proximal tubule

  2. Glomerular Filtration Rate is the fluid volume filtered by the glomerulus over time, which is approximately 180 liters per day

  3. Substances filtered from the blood enter the capsule including water, peptides, small proteins, salts, sugars, urea, metabolic waste, and drugs/drug metabolites

  4. Most drugs are filtered, with some exceptions such as monclonal antibodies and drugs that bind to large plasma proteins
• Tubular secretion (OATs and OCTs)

  1. Only 20% of renal plasma flow is filtered through the glomerulus, and the remaining 80% of plasma containing 80% of the drug passes on the peritubular capillaries surrounding the kidney tubules

  2. Drugs are selectively transported from the capillary into the tubule by two carrier systems: Organic Anion Transporters (OATs) and Organic Cation Transporters (OCTs)

  3. OATs transport acidic drugs in negatively charged anionic form, while OCTs transport basic drugs in positively charged cationic form

  4. OATs and OCTs are relatively non-selective for appropriately charged drugs and can transport drugs against electrochemical gradients
• Tubular re-absorption


  1. 99% of the fluid filtered by the glomerulus into the kidney tubule is reabsorbed by passive diffusion

  2. Some drug molecules diffuse freely back across the tubule alongside water, resulting in only 1% of the drug leaving via urine

  3. Lipophilic/non-polar drugs in the tubule are extensively reabsorbed into the plasma, whereas polar drugs/drug metabolites are poorly reabsorbed and highly concentrated in the urine
• Ion trapping


  • Drugs exist in ionized and non-ionized forms
  • Ionized drugs cannot freely diffuse across membranes, while non-ionized forms can be more lipid soluble
  • Changes in pH can alter the ionization of drugs
• Urinary alkalinization


  Causes increased excretion of acidic drugs and decreased excretion of basic drugs
• Urinary acidification


  Causes increased excretion of basic drugs and decreased excretion of acidic drugs
• Mechanism: At lower pH, acidic drugs become ionized and cannot return to plasma, leading to their excretion via urine. Conversely, at higher pH, basic drugs become ionized and are excreted via urine.
• Drug binding to plasma proteins


  • Most drugs that enter systemic circulation can bind to plasma proteins, with the most abundant plasma protein being albumin
  • Drugs bind reversibly and non-specifically to plasma proteins, acting as a long-term drug reservoir
  • Drug binding to plasma proteins also reduces the free plasma concentration of the drug, potentially requiring a higher dosage to achieve the desired therapeutic effect
  • Plasma protein concentration is decreased in elderly and malnourished individuals, which can impact drug binding and distribution
• Role of albumin in drug binding

  • Albumin, a major plasma protein, is substantially larger than the molecules typically filtered by the glomerulus in the kidney
  • Despite its size, albumin does not block glomerular filtration because kidney cells transport albumin using the neonatal Fc receptor (FcRn)
  • FcRn is involved in the recycling of serum albumin and IgG, preventing glomerular filtration blockage and increasing the half-life of albumin and IgG
• Drug interactions and plasma protein binding

  • If a second drug has a higher affinity for plasma proteins than the first drug, it will outcompete the first drug, leading to an increase in the plasma concentration of the free first drug
  • This competition for binding to plasma proteins can impact the distribution and effectiveness of drugs in the body
• Tubular secretion is the most efficient way of removing drugs that bind to plasma proteins, compared to glomerular filtration.
• Selective transport of free drug by carrier in tubular secretion reduces the plasma concentration of the free drug, shifting the equilibrium and allowing the drug to be transported out of the body.