Describe the role of the kidney in drug excretion and the factors affecting this (60% marks). Briefly outline how you would alter the dosing of a drug with high renal excretion in a patient with renal impairment (40% marks).
It was expected candidates would expand on the role of the kidney in the excretion of drugs and
metabolites. A statement that referred to the classical features of drugs that undergo renal
excretion (eg polarity, lipid solubility, size and protein binding, drug metabolites) and a definition
of renal clearance was expected and would have provided an excellent introduction to any
answer. It was then expected that candidates would mention, in some detail, the processes of
filtration and secretion (both active and passive and both proximal and distal along the renal
tubules). The question also asked for factors that affect renal drug excretion, for example, a
reduction in GFR or alteration in protein binding. An approach to alterations of dosing would
require some consideration of assessing degree of dysfunction (GFR estimation / calculation)
then an understanding that it would not impact on loading doses but would influence subsequent
dosing of renal cleared drugs. Plasma monitoring provides useful information for some drugs,
particularly those with a narrow therapeutic index.
This question closely resembles Question 8 from the first paper of 2010. The pass rate in 2010 was 0%. This year, it improved to 52%. The rather detailed and extensive college comment to a considerable extent illuminates the thinking of the examiners. On the basis of this, the following suggested answer is offered:
a) Role of the kidney in drug clearance
b) Dose adjustment for renal impairment
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.