L38-39 Excretion

• Renal Clearance


  The proportionality factor that relates the renal elimination rate of a drug with the drug concentration in blood (plasma)
• Renal Clearance


  Rate of Renal Elimination = Renal Clearance x Cdrug
• Renal Clearance


  Volume of fluid (blood, plasma) that is completely cleared of drug by the kidneys per unit time
• Renal Clearance


  • 100 mL /min, it means that the kidneys can completely clear all the drug present in 100 mL of plasma (blood) every minute
• Total Clearance


  1. Total Cl= Renal Clearance + Hepatic clearance

  2. Total Cl= ∑clearanceorgan
• Renal Clearance of drug I and drug II

  The steeper the slope the greater the renal clearance ∴ ClI >ClII
• Renal Clearance and Renal Excretion Rate

  For a same plasma concentration of drugs I and II, the excretion rate is greater for drug I
• Renal Extraction Ratio (ER)


  • The fraction of a drug passing by the kidneys which is eliminated by the kidneys, normally excreted into urine
  • The ratio between the rate of renal elimination and the rate of drug presentation to the kidneys
• Renal Clearance (ClR)


  • The ratio between the elimination rate by the organ and the incoming concentration
  • The volume of blood entering the kidney from which all the drug is removed per unit time
• High Renal Extraction Ratio

  • ER0.7
  • Renal clearance approaches renal blood flow
• Low Renal Extraction Ratio

  • ER0.3
• Renal excretion in healthy subjects is usually less variable than hepatic metabolism
• Kidneys


  • Receives ~1.2L/min blood
  • Nephron=basic functional unit
  • Secretion of urine occurs here
  • Maintains water and electrolyte balance
  • Hormone secretion
  • Blood pressure
  • Removal of: metabolic waste and foreign substances
• Nephron


  • 1 to 1.5 million nephrons per kidney
  • Glomerulus + proximal tubule + loop of Henle + distal tubule + collecting tubule
  • Filters, conserve useful materials, eliminate waste, toxic, foreign materials and to regulate water loss
• Glomerular Filtration


  1. The glomerulus filters 10% of its blood supply

  2. This filtration is unidirectional

  3. Process aided by hydraulic pressure exerted by arterial blood

  4. Kidneys receive 20-25% of cardiac input, 1.2 L of blood /min

  5. 120 mL/min are filtered (GFR or glomerular filtration rate), that is, 10% of 1.2 L/min
• Molecules dissolved in blood (plasma)


  • Ionized and non-ionized molecules are filtered
  • MW: < 2000 filtered easily, > 20000 filtration falls sharply
  • No albumin is usually found in this ultra filtrate, only unbound drugs are filtered
• Tubular Absorption


  1. Passive reabsorption: occurs all along the nephron

  2. 99% of filtered water is reabsorbed

  3. Aims: conservation of water. Electrolytes are also recovered

  4. Only 1-2 ml/min of urine is formed

  5. Active reabsorption: mediated by transporters at the proximal tubule: Vitamins B & C, glucose, amino acids and some drugs
• Passive Reabsorption


  Effect of ionisation (pH and weak acids/bases), lipophilicity
• Tubular Renal Secretion


  1. Active process mediated by carriers

  2. Carriers are not very specific and transport a wide variety of substances: Anions secreting systems (acids), Cation secreting systems (bases)

  3. Highly efficient and fast process for good substrates (high ER): completely removed from drug even if they are bound to plasma proteins or to red blood cells

  4. Dependent on renal blood flow
• Carrier Systems


  • Interactions: Probenecid competes with penicillin for the same carrier and decreases the active secretion and Clrenal.of the drug
  • Transporters can become saturated – non-linear kinetics
• Mechanisms of Renal Excretion

  1. Glomerular filtration: increases renal clearance

  2. Reabsorption, decreases renal clearance

  3. Secretion, increases renal clearance
• Creatinine


  • An endogenous substance completely unbound in plasma and (~) only eliminated by glomerular filtration
  • ClCr = 120 ml/min = GFR
• Creatinine Clearance (ClCr)


  • Marker of renal function (GFR)
  • Depends on: Rate in (muscle metabolism), Rate out (renal excretion, primarily by glomerular filtration)
• Stages of Renal Failure Progression

  1. Loss of 'renal reserve'

  2. Renal insufficiency

  3. Chronic renal failure

  4. End-stage renal failure
• Factors Modifying Passive Reabsorption

  • Urine flow rate
  • Passive permeability properties of the drug: MW, P (partition coefficient), Fraction ionised: consider urine pH and pKa of the drug