Clinical Pharmacokinetics

, Volume 57, Issue 10, pp 1267–1293 | Cite as

Complex Drug–Drug–Gene–Disease Interactions Involving Cytochromes P450: Systematic Review of Published Case Reports and Clinical Perspectives

  • Flavia Storelli
  • Caroline Samer
  • Jean-Luc Reny
  • Jules Desmeules
  • Youssef Daali
Systematic Review


Drug pharmacokinetics (PK) is influenced by multiple intrinsic and extrinsic factors, among which concomitant medications are responsible for drug–drug interactions (DDIs) that may have a clinical relevance, resulting in adverse drug reactions or reduced efficacy. The addition of intrinsic factors affecting cytochromes P450 (CYPs) activity and/or expression, such as genetic polymorphisms and diseases, may potentiate the impact and clinical relevance of DDIs. In addition, greater variability in drug levels and exposures has been observed when such intrinsic factors are present in addition to concomitant medications perpetrating DDIs. This variability results in poor predictability of DDIs and potentially dramatic clinical consequences. The present review illustrates the issue of complex DDIs using systematically searched published case reports of DDIs involving genetic polymorphisms, renal impairment, cirrhosis, and/or inflammation. Current knowledge on the impact of each of these factors on drug exposure and DDIs is summarized and future perspectives for the management of such complex DDIs in clinical practice are discussed, including the use of advanced Computerized Physician Order Entry (CPOE) systems, the development of model-based dose optimization strategies, and the education of healthcare professionals with respect to personalized medicine.


Compliance with Ethical Standards


No funding was received for the preparation of this manuscript.

Conflict of interest

Flavia Storelli, Caroline Samer, Jean-Luc Reny, Jules Desmeules and Youssef Daali declare no conflicts of interest.

Supplementary material

40262_2018_650_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 18 kb)


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Flavia Storelli
    • 1
    • 2
  • Caroline Samer
    • 1
    • 3
    • 4
  • Jean-Luc Reny
    • 3
    • 5
  • Jules Desmeules
    • 1
    • 2
    • 3
    • 4
  • Youssef Daali
    • 1
    • 2
    • 3
    • 4
  1. 1.Division of Clinical Pharmacology and Toxicology, Geneva University HospitalsUniversity of GenevaGenevaSwitzerland
  2. 2.Geneva-Lausanne School of PharmacyUniversity of GenevaGenevaSwitzerland
  3. 3.Faculty of MedicineUniversity of GenevaGenevaSwitzerland
  4. 4.Swiss Center for Applied Human ToxicologyGenevaSwitzerland
  5. 5.Department of Internal Medicine, Rehabilitation and Geriatrics, Geneva University HospitalsUniversity of GenevaGenevaSwitzerland

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