Question 8

College Answer

Drug characteristics that might influence the renal excretion processes include charge, size, 
solubility, and binding to specific structures or protein. Whether the drug is unchanged versus 
metabolised can influence these factors. 
This question tests core knowledge of pharmacology principles and should be answered with 
equations, graphs or simple clear descriptions of physical and chemical principles. Extended 
examples and hedged statements about “influencing” without the direction, magnitude and 
necessary conditions for the influence did not score marks. 

Discussion

The college answer being unstructured and incomplete, the trainee is left to construct his own in a vacuum devoid of senior guidance. A well-structured answer would probably benefit from splitting the characteristics into the three major components which make up renal clearance, those being glomerular filtration, active secretion, passive reabsorption and intrinsic renal metabolism.

Drug characteristics which influence its glomerular filtration

• Protein binding: Only the free fraction of the drug is filtered, which means that highly protein bound drugs are poorly filtered in the glomerulus
• Charge:  Theoretically the negatively charged glomerular basement membrane should repel negatively charged drugs, but practically this does not seem to play much of a role.
• Size: Molecules less than 30 Angstroms are freely filtered at the glomerulus. According to classical works by Bott and Richards (1941) the molecular weight limit is somewhere around 14 kDa.

Drug characteristics which influence its active secretion

• Protein binding (only the free fraction is available for uptake from the peritubular capillary blood)
• Competition between substrates eligible for the same transporter
• Concentration of the drug (these transporters are saturable)

Drug characteristics which influence its passive resorption

• Molecule size (smaller molecules are reabsorbed more easily)
• Drug concentration in the urine (which is dependent mainly on urine flow rate)
• pKa of the drug, which influences its ionisation (i.e. ionised vs. non-ionised fractions) - only the non-ionised fraction of the drug is absorbed by passive diffusion through the lipid bilayer

Other drug characteristics which influence renal clearance

• Chemical resemblance to "natural" substrates can make the drug eligible for reabsorption by active transport
• Susceptibility to renal metabolic enzymes, eg. in the case of peptides and imipenem

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