Drug Excretion

• Drug metabolism


  Chemical transformation of a drug into one or more products within the body
• Drug excretion


  The physical processes that lead to the irreversible removal of a drug and its metabolites from the body
• Drug elimination


  Drug metabolism and drug excretion
• Drug elimination


  The removal of drug from the body through metabolic and/or excretory processes
• A.D.M.E


  • Absorption
  • Distribution
  • Metabolism
  • Excretion
• Drug elimination is made up of 75% drug metabolism mediated by CYP450 and drug excretion
• Routes of Drug excretion

  • urine (kidneys)
  • faeces (bile)
  • breast milk - minor route and can pass from mother to baby
  • expired air (lungs)
  • hair
  • skin/sweat
• Hydrophilic drugs do not require hepatic metabolism
• Factors that influence renal excretion

  • Molecular weight and size
  • Drug concentration
  • Urine pH
  • Plasma protein binding
  • Renal blood flow
  • Impaired renal Function
  • Transporters
• Non-steroidal and anti-inflammatory drugs reduce renal function
• Types of renal excretion

  • Glomerular Filtration
  • Passive reabsorption
  • Active tubular Secretion
• Glomerular Filtration


  • 20% of renal plasma flow is filtered thru glomerular capillaries (GFR=120mL/min and declines due to aging or disease)
  • Only small and free drugs can pass thru glomerular capillaries into the filtrate
  • Altered plasma protein binding can influence filtration
• GFR


  Glomerular filtration rate
• Fu


  Fraction of drugs unbound in plasma
• eGFR


  Estimated glomerular filtration rate - measure of blood creatinine level
• Impaired renal function leads to increased blood creatinine level
• Passive reabsorption


  • Most filtrate returns to circulation through peritubular capillaries (1% becomes urine)
  • Water reabsorption leads to drug concentration increase in the filtrate
  • Passive diffusion - small, lipophilic and unionised drugs
  • Transporter-mediated (e.g., PEPT2 and peptide-like drugs)
  • Urine pH affects drug ionisation and reabsorption
• Peritubular capillaries


  Tiny blood vessels in the kidneys that filter waste from blood and reabsorb nutrients
• Urine pH affects drug ionisation and reabsorption
• Salicylate overdose


  1. Aspirin or methyl salicylic acid overdose

  2. Intravenous sodium bicarbonate (an alkalinising agent) injected

  3. Increased urine pH

  4. Increased salicylic acid ionisation

  5. Decreased reabsorption of salicylate
• Only unionised molecules can cross cell membranes
• Active tubular secretion


  • Occurs predominantly in proximal tubules
  • Mediated by transporters
• Basolateral membrane


  Cell membrane oriented away from the lumen of the tubule, contains solute carrier (SLC) transporters
• Apical membrane


  Cell membrane oriented towards the lumen, contains solute carrier (SLC) transporters and ATP-binding cassette (ABC) transporters
• Lumen


  The space within the body's tracts, tubes, cavities, and cells
• Solute carrier (SLC) transporters

  • SLC22A6 - OAT1 (organic anion transporter 1)
  • SLC22A8 - OAT3 (organic anion transporter 3)
• ATP-binding cassette (ABC) transporters


  • ABCB1 - MDR1 (multidrug resistance protein 1) or P-gp (P-glycoprotein)
  • ABCC2 - MRP2 (multidrug resistance-associated protein 2)
  • ABCG2- BCRP (breast cancer resistance protein)
• MDR1


  Transports large lipophilic cationic compounds and neutral compounds, multidrug resistance protein 1
• Transporter-mediated active secretion (basolateral membrane)

  • OAT1 and OAT3 have overlapping substrate specificity
• Transporter-mediated active secretion (OAT1/3-mediated drug excretion)


  1. Example: cephalexin (a cephalosporin drug)

  2. Mostly excreted unchanged via urine through glomerular filtration and active tubular secretion

  3. Drug-drug interaction: probenecid (an OAT1/OAT3 inhibitor; pharmacokinetic enhancer) co-administration increases Cmax and AUC
• Hepatobiliary excretion


  • Hepatocytes produce and secrete bile
  • Bile is stored in the gallbladder and drained into the bile duct then duodenum
  • Drug excreted into bile
  • Glucuronides are concentrated in bile
• Drug metabolising enzymes produce conjugated metabolites
• Basolateral membrane transporters


  Liver-specific OATP1B1/1B3 - uptake of drugs and metabolites into hepatocytes
• Apical membrane transporters


  Efflux transporters - eliminate large and polar molecules into bile
• Enterohepatic recirculation


  1. Lipophilic drugs (e.g., morphine) undergo absorption

  2. Hepatic metabolism

  3. Conjugates excreted into bile

  4. Glucuronides in the GI tract hydrolysed by ß-glucuronidase (expressed by GI bacteria) to generate unconjugated drug

  5. Unconjugated drug reabsorbed back into systemic circulation
• Enterohepatic recirculation of morphine leads to prolonged effects and long half-life
• Breast milk is a minor route of drug excretion, most drugs enter via passive diffusion
• Individual variation in drug response

  Differences in response between individuals to the same dose of a drug
• Individual variation in drug response: intrinsic factors

  • Genetics
  • Age
  • Sex
  • Disease status or physiological conditions such as pregnancy
• Individual variation in drug response: extrinsic factors


  • Concomitant medications
  • Diet
  • Exposure to chemicals and other environmental causes