Describe the characteristics of a drug that influence its excretion by the kidneys

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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

References

Miners, J. O., et al. "The Role of the Kidney in Drug Elimination: Transport, Metabolism and the Impact of Kidney Disease on Drug Clearance." Clinical Pharmacology & Therapeutics (2017).

Mahasen, Laila M. Aboul. "Evolution of the Kidney." Anatomy Physiol Biochem Int J 1(1) : APBIJ.MS.ID.555554 (2016)

Brater, D. Craig. "Measurement of renal function during drug development." British journal of clinical pharmacology 54.1 (2002): 87-95.

Levy, Gerhard. "Effect of plasma protein binding on renal clearance of drugs." Journal of pharmaceutical sciences 69.4 (1980): 482-483.

Regårdh, Carl G. "Factors contributing to variability in drug pharmacokinetics. IV. Renal excretion." Journal of Clinical Pharmacy and Therapeutics 10.4 (1985): 337-349.

Miner, Jeffrey H. "The glomerular basement membrane." Experimental cell research 318.9 (2012): 973-978.

Elwi, Adam N., et al. "Renal nucleoside transporters: physiological and clinical implications This paper is one of a selection of papers published in this Special Issue, entitled CSBMCB—Membrane Proteins in Health and Disease." Biochemistry and cell biology 84.6 (2006): 844-858.

Nigam, Sanjay K., et al. "Handling of drugs, metabolites, and uremic toxins by kidney proximal tubule drug transporters." Clinical journal of the American Society of Nephrology 10.11 (2015): 2039-2049.

Bendayan, Reina. "Renal drug transport: a review." Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 16.6 (1996): 971-985.

Birnbaum, Jerome, et al. "Carbapenems, a new class of beta-lactam antibiotics: Discovery and development of imipenem/cilastatin." The American journal of medicine 78.6 (1985): 3-21.

Lohr, James W., Gail R. Willsky, and Margaret A. Acara. "Renal drug metabolism." Pharmacological Reviews 50.1 (1998): 107-142.

Bott, Phyllis A., and A. N. Richards. "The passage of protein molecules through the glomerular membranes." Journal of Biological Chemistry 141.1 (1941): 291-310.