Mechanisms of pharmacokinetic drug-drug interactions

By Alex Yartsev - 05/02/2018
Last updated 16/07/2022 - 20:47
 Topic: Variability in drug response

This chapter is directly related to Section D(ii) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "classify and describe mechanisms of drug interaction". It is also vaguely related to the learning objectives of Section C which exhorts them develop "a general understanding of how drugs work, ... including ... drug interactions". In short, interactions between drugs can be classified as pharmacokinetic and pharmacodynamic. Pharmacodynamic drug-drug interactions are briefly described in another chapter. Here, the focus is on the mechanisms by which drugs interfere with each other's absorption, distribution, metabolism and elimination.

The topic of drug-drug interactions has appeared three times, in three identical questions:

All of these asked the candidates to "classify and describe the mechanisms of drug interactions with examples." The question was not specific for pharmacokinetic interactions, but these would surely form the bulk of the answer.  Certainly they form the bulk of the published literature (comparatively speaking; one needs to dive deep into obscure textbooks to find good articles on pharmacodynamic drug-drug interactions). Of which, the best and most detailed article is probably the (free, PubMedable) paper by Cascorbi (2012). Unless otherwise referenced, the examples come straight from this paper. 

Pharmacokinetic Drug-Drug interactions
Mechanism Examples
Absorption interactions

Formation of insoluble complexes
  • The decreased bioavailability of bisphosphonates when calcium is co-administered

Inhibition of active transporters
  • Inhibition of metformin uptake by repaglinide interfering with the organic cation transporter OCT1

Inhibition of efflux transporters
  • The effect of verapamil on the P-glycoprotein efflux pump reduces the efflux of digoxin; ergo the concentration of digoxin increases
  • The effect of rifampicin on the P-glycoprotein efflux pump increases its activity, thereby increasing gut clearance of cyclosporine 
Distribution interactions

Competition for transport protein binding sites
  • Phenytoin and valproate compete for the same protein binding sites, which tends to displace phenytoin (Perucca et al, 1980)
Metabolic interactions

Competition for the same CYP450 enzymes
  • Macrolides, inhibiting the metabolism of warfarin (and about half of all other medically interesting drugs) by competing for CYP450 3A4

Inhibition or induction of metabolic enzymes
  • The effect of carbamazepine, which increases the rate of warfarin and oral contraceptive metabolism 
  • The inhibition of metabolic pathways can also paradoxically decrease the bioavailability if those enzymes convert a prodrug into the active from (eg. tamoxifen)
Interactions influencing elimination

Competition for active transport
  • The effect of probenecid is to decrease the actve secretion of β-lactams and  cephalosporins

Interference with solubility
  • Increased ion trapping of salicylate in alkaline urine due to the use of acetazolamide

References

Palleria, Caterina, et al. "Pharmacokinetic drug-drug interaction and their implication in clinical management." Journal of research in medical sciences: the official journal of Isfahan University of Medical Sciences 18.7 (2013): 601.

Huang, Shiew-Mei. "Drug-drug interactions." Applications of Pharmacokinetic Principles in Drug Development. Springer, Boston, MA, 2004. 307-331.

Snyder, Ben D., Thomas M. Polasek, and Matthew P. Doogue. "Drug interactions: principles and practice." Australian prescriber 35.3 (2012): 85-8.

Perucca, E., et al. "Interaction between phenytoin and valproic acid: plasma protein binding and metabolic effects." Clinical Pharmacology & Therapeutics 28.6 (1980): 779-789.

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