In vivo modulation of CYP enzymes by quinidine and rifampin

Clin Pharmacol Ther. 2000 Oct;68(4):401-11. doi: 10.1067/mcp.2000.110561.


Background: The metabolism of drugs and other xenobiotics is mediated by enzymes whose activities can be modulated by different compounds. The activities of these modulators have the potential to be used to optimize drug action, prevent toxicity, or identify the enzymes involved in a reaction. This approach requires that selective agents be used for specific enzymes. However, selectivity of action has been poorly characterized in vivo.

Methods: This study investigated the effect of 3 and 28 days of treatment with quinidine (200 mg daily) and rifampin (INN, rifampicin) (600 mg daily) on the activities of four cytochrome P450 enzymes and N-acetyltransferase in 28 healthy young male volunteers divided into three groups with a cocktail of drug probes used, including caffeine, mephenytoin, debrisoquin (INN, debrisoquine), and dapsone.

Results: Quinidine selectively and almost completely inhibited the activity of CYP2D6 from day 3 through day 28 without affecting any other enzymes. Rifampin showed evidence of time-dependent induction of the activities of all measured oxidative routes of metabolism but decreased the acetylation ratio in fast acetylators. The quinidine/rifampin combination resulted in selective CYP2D6 inhibition and induction of all other enzymes evaluated over this time period, suggesting that predictable complex interactions occur with the drug combination.

Conclusions: These observations illustrate the value of simultaneous assessment of the effect of modulators on the activities of multiple specific enzymes with the drug cocktail approach.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylation / drug effects
  • Administration, Oral
  • Adrenergic alpha-Antagonists / administration & dosage
  • Adrenergic alpha-Antagonists / pharmacology*
  • Adult
  • Anti-Arrhythmia Agents / pharmacology
  • Antibiotics, Antitubercular / pharmacology
  • Anticonvulsants / pharmacology
  • Aryl Hydrocarbon Hydroxylases*
  • Caffeine / pharmacology
  • Central Nervous System Stimulants / pharmacology
  • Cytochrome P-450 CYP1A2 / metabolism
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2E1 / metabolism
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dapsone / pharmacology
  • Debrisoquin / pharmacology
  • Drug Administration Schedule
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Male
  • Mephenytoin / pharmacology
  • Mixed Function Oxygenases / metabolism
  • Quinidine / administration & dosage
  • Quinidine / pharmacology*
  • Reference Values
  • Rifampin / administration & dosage
  • Rifampin / pharmacology*
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / metabolism
  • Theophylline / pharmacology


  • Adrenergic alpha-Antagonists
  • Anti-Arrhythmia Agents
  • Antibiotics, Antitubercular
  • Anticonvulsants
  • Central Nervous System Stimulants
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Caffeine
  • Dapsone
  • Cytochrome P-450 Enzyme System
  • Theophylline
  • Mixed Function Oxygenases
  • Steroid Hydroxylases
  • Cytochrome P-450 CYP2E1
  • Aryl Hydrocarbon Hydroxylases
  • CYP1A2 protein, human
  • CYP2C19 protein, human
  • CYP3A protein, human
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • Steroid 16-alpha-Hydroxylase
  • Quinidine
  • 1,7-dimethylxanthine
  • Mephenytoin
  • Rifampin
  • Debrisoquin