Study On Effect Of Imperatorin And Isoimperatorin On The Cytochrome P4501A2-mediated Metabolism Of Theophylline And Its8-hydroxyiation In Rats

Objectives：With theophylline as CYP1A2in body probe drugs, study the effects ofimperatorin and isoimperatorin on the pharmacokinetic of theophylline and themetabolites of1,3-dimethyluric acid that cytochrome P4501A2-mediated8-hydroxylation of theophylline, which is after intravenous administration oftheophylline with single or multiple of imperatorin or isoimperatorin pretreatment. Toinvestigate the effects of imperatorin and isoimperatorin on the pharmacokineticof theophylline in rats and that with the relationship between the activity of CYP1A2and8-hydroxylation metabolic pathways, which provided the experimental referencesfor the rational clinical use of imperatorin, isoimperatorin as well as thecorresponding proprietary Chinese medicine.Methods：1. To set up the HPLC analyse method of TP and1,3-DMU at the same time.2. Study the effects of imperatorin on the pharmacokinetic of theophylline andthe metabolites of1,3-dimethyluric acid that cytochrome P4501A2-mediated8-hydroxylation of theophylline in rats respectively, which is after intravenousadministration of theophylline with or without single or multiple different dose ofimperatorin pretreatment.3. Study the effects of isoimperatorin on the pharmacokinetic of theophyllineand the metabolites of1,3-dimethyluric acid that cytochrome P4501A2-mediated8-hydroxylation of theophylline in rats respectively, which is after intravenousadministration of theophylline with or without single or multiple different dose ofisoimperatorin pretreatment.4. Comparing to the effects of imperatorin and isoimperatorin on thepharmacokinetic of theophylline and the metabolites of1,3-dimethyluric acid thatcytochrome P4501A2-mediated8-hydroxylation of theophylline.And explore therelationship between the effects of imperatorin and isoimperatorin on the CYP1A2activity and cytochrome P4501A2-mediated8-hydroxylation. Results:1. Establishing the HPLC analyse method of TP and1,3-DMU at the same time.2. Imperatorin has inhibitingt effects on the pharmacokinetic of theophylline andthe metabolites of1,3-dimethyluric acid that cytochrome P4501A2-mediated8-hydroxylation of theophylline, which is after intravenous administration oftheophylline with single or multiple different dose of imperatorin pretreatment.Andthe inhibiting effect by imperatorin with time-dependent and dose-dependent pattern.3. Isoimperatorin has inhibiting effects on the pharmacokinetic of theophyllineand the metabolites of1,3-dimethyluric acid that cytochrome P4501A2-mediated8-hydroxylation of theophylline, which is after intravenous administration oftheophylline with single or multiple different dose of isoimperatorin pretreatment.And the inhibiting effect by isomperatorin with time-dependent and dose-dependentpattern.4. Imperatorin and Isoimperatorin inhibit the pharmacokinetic of theophyllineand the metabolites of1,3-dimethyluric acid that cytochrome P4501A2-mediated8-hydroxylation of theophylline,but their dieffrences of effect are not significantly.Conclusions:1. We have established the sensitive HPLC analyse method of TP and1,3-DMUin plasma of rats.2. Imperatorin and Isoimperatorin inhibit the TP metabolites in rats, which hasthe relationship with the activity of CYP1A2decreased and result in8-hydroxylationof theophylline reduced.