Alteration of the pharmacokinetics of theophylline by rutaecarpine, an alkaloid of the medicinal herb Evodia rutaecarpa, in rats

J Pharm Pharmacol. 2005 Feb;57(2):227-32. doi: 10.1211/0022357055489.


Rutaecarpine is a main active alkaloid present in the medicinal herb, Evodia rutaecarpa. The cytochrome P450 (CYP) 1A2 substrate, theophylline, is an important therapeutic agent for the treatment of asthma, but has a narrow therapeutic index. To evaluate the pharmacokinetic interaction of theophylline with rutaecarpine, the effects of rutaecarpine on CYP1A2 activity and theophylline pharmacokinetics were investigated. Oral treatment of Sprague-Dawley rats with 50 mg kg(-1) rutaecarpine for three days through a gastrogavage caused a 4- and 3-fold increase in liver microsomal 7-ethoxyresorufin O-deethylation (EROD) and 7-methoxyresorufin O-demethylation activity, respectively. In the kidney, rutaecarpine treatment caused a 3-fold increase in EROD activity. In the lungs, EROD activity was elevated from an undetectable to a detectable level by rutaecarpine. Pharmacokinetic parameters of theophylline were determined using a microdialysis sampling method. Rutaecarpine pre-treatment increased the clearance of theophylline in a dose-dependent manner. Pre-treatment of rats with 50 mg kg(-1) rutaecarpine caused a 3-fold increase in theophylline clearance and a 70%, 68% and 68% decrease in the area under the concentration-time curve (AUC), mean residence time (MRT) and half-life, respectively. These results demonstrated that rutaecarpine treatment elevated CYP1A2 catalytic activity and theophylline excretion in rats. In patients taking theophylline, adverse effects might be noticed when a rutaecarpine-containing herbal preparation is used concomitantly.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / administration & dosage
  • Alkaloids / chemistry
  • Alkaloids / isolation & purification*
  • Alkaloids / pharmacokinetics
  • Alkaloids / pharmacology
  • Animals
  • Area Under Curve
  • Cytochrome P-450 CYP1A1 / drug effects
  • Cytochrome P-450 CYP1A1 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Evaluation, Preclinical / methods
  • Drug Interactions*
  • Enzyme Induction
  • Evodia / chemistry*
  • Half-Life
  • Indole Alkaloids
  • Intubation, Gastrointestinal
  • Kidney / chemistry
  • Kidney / drug effects
  • Kidney / metabolism
  • Lung / chemistry
  • Lung / drug effects
  • Lung / metabolism
  • Male
  • Microdialysis / methods
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Oxazines / metabolism
  • Plants, Medicinal / chemistry*
  • Quinazolines
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Theophylline / administration & dosage
  • Theophylline / blood
  • Theophylline / pharmacokinetics*
  • Time Factors


  • Alkaloids
  • Indole Alkaloids
  • Oxazines
  • Quinazolines
  • 7-methoxyresorufin
  • rutecarpine
  • Theophylline
  • Cytochrome P-450 CYP1A1