Alteration of the pharmacokinetics of theophylline by rutaecarpine, an alkaloid of the medicinal herb Evodia rutaecarpa, in rats.
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.
Ueng
Yune-Fang
YF
National Research Institute of Chinese Medicine, Taipei, Taiwan, R.O.C. ueng@nricm.edu.tw
Tsai
Tung-Hu
TH
Don
Ming-Jaw
MJ
Chen
Ruei-Ming
RM
Chen
Ta-Liang
TL
D000470:Alkaloids / Q000008:administration & dosage / Q000737:chemistry / Q000302:isolation & purification* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D004790:Enzyme Induction; D032086:Evodia / Q000737:chemistry*; D006207:Half-Life; D026121:Indole Alkaloids; D007441:Intubation, Gastrointestinal; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017551:Microdialysis / Q000379:methods; D008862:Microsomes, Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D010078:Oxazines / Q000378:metabolism; D010946:Plants, Medicinal / Q000737:chemistry*; D011799:Quinazolines; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013806:Theophylline / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors; D052999:Quinazolinones
D000470:Alkaloids; D019363:Cytochrome P-450 CYP1A1; D026121:Indole Alkaloids; D010078:Oxazines; D011799:Quinazolines; D013806:Theophylline; C076580:7-methoxyresorufin; C028632:rutecarpine; D052999:Quinazolinones