The Pharmacokinetics And Drug Metabolism Of Main Compounds In Mang-Go-Zhi-Ke Tablets In Rats

Objrctive:Mang-Guo-Zhi-Ke tablets were developed by GuangxiuniversityoftraditionalmedicinePharmaceutical Factory and widely used in clinic.The preparation uses the extract of the mango(Mangifera indica L.)leaves as the main raw material together with two western medicine components of chlorphenamine maleate and sodium houttuyfonate.Mang-Guo-Zhi-Ke tablets have the effect of dispersing lung qi,dissipating phlegm,relieving cough and asthma.It is mainly used for cough,asthma,phlegm and other symptoms,especially the chronic bronchitis in clinical treatment.However,the usage and dosage of Mang-Guo-Zhi-Ke tablets are only based on the clinical experience.The material basis of the extract of mango leaves is not clear enough,and its main components in vivo process is not reported,resulting in the limits to the safety of administration.As a result,it is necessary that the main components of mangiferin,kaempferol,quercetin,gallic acid,p-hydroxybenzoic acid,chlorpheniramine maleate in vivo process study should be conducted based on technology of LC-MS.Method: An UHPLC-TQ-MS/MS method was developed and used to simultaneously determine kaempferol,quercetin,mangiferin,p-hydroxybenzoic acid,gallic acid and chlorpheniramine maleate in rat plasma after oral administration of MGZKTs;An UHPLC-TQ-MS/MS method was developed and used to simultaneously determine kaempferol,quercetin,mangiferin,p-hydroxybenzoic acid,gallic acid and chlorpheniramine maleate in rat heart,liver,speen,lung,kidney after oral administration of MGZKTs at 15 min,30 min,and 60 min;The ultra-high performance liquid chromatography-LTQ Orbitrap mass spectrometric(UHPLC-LTQ-Orbitrap-MS)and mass defect filter techniques were applied to analyze the metabolites of kaempferol,quercetin,mangiferin,p-hydroxybenzoic acid,gallic acid,chlorpheniramine maleate and sodium houttuyfonate in rat plasma,bile,urine and feces;The ultra-high performance liquid chromatography-LTQ Orbitrap mass spectrometric(UHPLC-LTQ-Orbitrap-MS)and mass defect filter techniques were applied to analyze the metabolites of kaempferol,quercetin,mangiferin,p-hydroxybenzoic acid,gallic acid,chlorpheniramine maleate and sodium houttuyfonate in rat plasma,bile,urine and feces;After oral administration of Mang-Guo-Zhi-Ke Tablets,urine and feces were taken at 6h,12 h,24h,48 h,72h.An UHPLC-TQ-MS/MS method was developed and used to simultaneously determine kaempferol,quercetin,mangiferin,p-hydroxybenzoic acid,gallic acid and chlorpheniramine maleate in rat urine and feces.Results:The method was successfully developed and fully validated to investigate the pharmacokinetics of MGZKTs.Each rat was intragastrically administered at a dosage of 400 mg/kg MGZKTs.The obtained calibration curves were linear in the concentration range of 1–1000 ng/mL for plasma(r >0.99).The accuracy and precision were within the accepted variable limits.Quercetin,p-hydroxybenzoic acid and kaempferol were absorbed rapidly and reached the peak concentration between 0.16 and 0.25 h;Mangiferin,quercetin,kaempferol,p-hydroxybenzoic acid,gallic acid,and chlorphenamine maleate were rapidly distributed in various tissues after oral administration of MGZKTs in rats.The content in tissues increased at first and then decreased.There are also bimodal phenomena in individual substances;there are 19 metabolites were detected and identified.these compounds were metabolized to the forms of methylation,glucuronidation,deglycosylation,hydroxylation and dehydration,demethylation,oxydation,glutathione conjugation(glutamate removal),glutathione conjugation,cysconjugation,hydroxylation,sulfation,in vivo.It provided referential information for effective material basis of Reduning in order to explore its process in vivo;Gallic acid and p-hydroxybenzoic acid are mainly excreted in the urine.The excretion of mangiferin occurs mainly in the urine.Kaempferol appears to mainly excreted in the feces.Conclusion: An UHPLC-TQ-MS/MS method was developed and used to simultaneously determine kaempferol,quercetin,mangiferin,p-hydroxybenzoic acid,gallic acid and chlorpheniramine maleate in rat plasma,fece,urine,bile,heart,liver,speen,lung,kidney after oral administration of MGZKTs.The method was successfully developed and fully validated to investigate the pharmacokinetics,tissue distribution,metabolites,exctretionof MGZKTs.Itmight provide evidence to reveal the in vivo process of Mang-Guo-Zhi-Ke tablets,and to guide clinical safe drug use.