Understanding cooperativity in human P450 mediated drug-drug interactions

Stephen G. Sligar, Ilia G. Denisov

Research output: Contribution to journalReview articlepeer-review


Multiple drugs can interact, often leading to adverse side effects. One well documented site for these interactions includes the group of cytochrome P450 monoxygenases. Several human hepatic systems are known to bind more than a single substrate molecule which can give rise to the terms "homotropic and heterotopic cooperativity" to define the resultant thermodynamic and kinetic properties observed in drug metabolism investigations. We provide a means for understanding and quantitating these drug-drug interactions by documenting the functional properties of the various states of the enzyme and show that, even in the absence of true binding cooperativity, significant non-Michaelis metabolic profiles are possible.

Original languageEnglish (US)
Pages (from-to)567-579
Number of pages13
JournalDrug Metabolism Reviews
Issue number2-3
StatePublished - Apr 2007


  • CYP3A4
  • Cytochrome P450
  • Dose-response function
  • Heterotropic Cooperativity
  • Homotropic cooperativity

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Pharmacology (medical)


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