Effect of decursinol angelate on the pharmacokinetics of theophylline and its metabolites in rats

• Published in: Food and chemical toxicology 2012-10, Vol.50 (10), p.3666-3672
• Main Authors: Chae, Jung-woo, An, Jung-hwa, Kang, Wonku, Ma, Jin yeul, Kwon, Kwang-il
• Format: Article
• Language: English
• Subjects: Animals; Area Under Curve; Benzopyrans - metabolism; Benzopyrans - pharmacokinetics; Biological and medical sciences; blood; Butyrates - metabolism; Butyrates - pharmacokinetics; caffeine; cytochrome P-450; Decursinol angelate; Drug Interactions; drug therapy; Half-Life; herbal medicines; Herb–drug interaction; liquid chromatography; Male; mass spectrometry; Medical sciences; metabolites; Molecular Structure; patients; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Reproducibility of Results; risk; Theophylline; Theophylline - blood; Theophylline - chemistry; Theophylline - metabolism; Theophylline - pharmacokinetics; toxicity; Toxicology
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2012.06.049

[Display omitted] ► Decursinol angelate (DA) inhibited the activities of CYP1A2. ► Almost 90% of theophylline is metabolized in liver by CYP1A2 and CYP2E1. ► The first study of DA - theophylline interaction was performed in rats. ► Pretreatment of DA affected the cytochrome P450 family of enzymes. ► DA significantly affected the PK parameters of theophylline and its metabolites. Herb-drug interactions represent a serious problem as herbal medicine is used extensively in the modern world. This study investigated the effects of decursinol angelate on the pharmacokinetics of theophylline, a typical substrate of the cytochrome P450 1A2 enzyme, in rats. After 3days of decursinol angelate pretreatment, on the fourth day, rats were administered decursinol angelate and theophylline concomitantly. Blood theophylline and its major metabolite [1-methylxanthine (1-MX), 3-methylxanthine (3-MX), 1-methyluric acid (1-MU), and 1,3-dimethyluric acid (1,3-DMU)] levels were monitored by liquid chromatography-tandem mass spectroscopy. The results indicated that theophylline clearance significantly decreased and the area under the concentration–time curve (AUC) increased in decursinol angelate (25mg/kg)-pretreated rats administered theophylline (10mg/kg). The elimination half-life (t1/2) of theophylline was increased by 20%. In the presence of decursinol angelate (25mg/kg), the pharmacokinetic parameters of three metabolites (1-MX, 1,3-DMU, and 1-MU) were significantly altered (half-life for 1-MU, and AUC24h for 1-MX, 1,3-DMU, and 1-MU). Our results suggest that patients receiving CYP1A2-metabolized drugs, such as caffeine and theophylline, should be advised of the potential herb-drug interaction to reduce the risk of therapeutic failure or increased toxicity of conventional drug therapy.