The kidneys are the most important excretion organ for hydrophilic drugs or polar metabolites. The biotransformation in the liver has resulted in increased water solubility of drugs and their metabolites (glucuronides and sulphate conjugates).
Excretion of drugs by the kidney is dependent on 3 main mechanisms:
- Glomerular filtration of unbound drug.
- Active tubular secretion of drug by transporters.
- Tubular reabsorption by passive diffusion following the concentration gradient.
The rate of drug elimination depends on the balance between filtration, secretion and reabsorption.
A renally cleared drug has a renal clearance of 100 mL/min in a healthy adult. The drug is bound for 83% to proteins in the blood plasma. Based on this information, which renal mechanism is largely responsible for elimination of this drug. Use a filtration rate of 120 mL/min for healthy adults.
Extra info: The unbound fraction of this drug (the fraction that can be excreted by glomerular filtration) is 0.17, thus the expected clearance by passive diffusion is around 20 ml/min (0.17 · 120). Since the observed filtration rate is much higher (120 mL/min), active tubular secretion is the primary route of elimination.
Cylcophosphamide is used for treatment of both solid and hematologic tumours. The drug has a renal clearance of 10.7 mL/min in a healthy adult. The drug is bound for 20% to proteins in the blood plasma. Based on this information, which renal mechanism is largely responsible for excretion (rate) of this drug? Use a glomerular filtration rate of 120 mL/min for healthy adults.
Extra info: The expected renal clearance would be GFR*(fraction unbound) = 120*0.8=96 mL/min. The actual clearance is much lower (10.7 mL/min), thus there should be an extensive amount of drug be reabsorbed in the tubule.