A Study Of The Drug Interaction Between Orange Juices And Isoniazid Based On Pharmacokinetics

Objective: Based on pharmacokinetics, the food-drug interaction(FDI) between orange juice and isoniazid(INH) had been researched.Methods: 1. HPLC and LC-MS methods were adopted to determine the contents of isoniazid(INH) and its metabolites acetyl isoniazid(Ac INH), isonicotinic acid(INA) in rat's plasma and liver tissue. 2.Groups of SD rats were orally taken INH and orange juice. The INH group was given INH(90 mg/kg). 30 minutes after the administration, the orange juice group was given juice(20 m L/kg). The plasma samples were collected at 10?20?30?45?60?75?90?120?150?180 min respectively. The contents of isoniazid of different groups were detected and analyzed. 3. Groups of SD rats were orally taken INH and orange juice for 30 days. The orange juice group was given juice(20 m L/kg) twice per day. The INH group was given INH(30 mg/kg) once per day. The orange juice combined INH group was given INH(30 mg/kg) and juice(20 m L/kg). The blank group fed equal volume of distilled water. At the last day, the dose of INH was 90 mg/kg. The plasma samples were collected at 10?20?30?45?60?75?90?120?150?180?210 min respectively. The contents of isoniazid, Ac INH and INA of different groups were detected. Gene expressions of transporters in duodenum and kidney were examined by RT-PCR. The metabolizing enzymes in liver which played key roles in metabolism of INH were examined by Western-blot. 4. Groups of SD rats were orally taken INH and orange juice for 60 and 180 days. The dosage regimen was the same as the previous. After the last administration, the plasma samples and liver tissues were collected at 10?20?30?45?60?75?90?120?150?180 min respectively. The contents of isoniazid in plasma samples were detected. And the contents of isoniazid, Ac INH and INA in liver tissues were analyzed. Gene expressions of transporters in duodenum and kidney were examined by RT-PCR. The metabolizing enzymes in liver which played key roles in metabolism of INH were examined by Western-blot.Results: 1. The methods were used to detect the concentration of INH and its metabolites Ac INH, INA in rat plasma and liver samples by HPLC and LC-MC. 2. The experiments found the orange juice can reduce the concentration of INH in rat plasma samples. 3. The further research found orange juice could influnce the concentration of INH and INA in rat plasma samples. And both of orange juice and INH could reduce the m RNA expression of secretion transporters BCRP, ATP8B1 in duodenum and MATE2-K in kidney. INH could increase the MRP4 m RNA expression in Kidney, and the protein expression of FAAH1, CYP2E1 and GST in liver. Orange juice could increase the protein expression of NAT2 and FAAH1 in liver. 4. The orange juice could increase not only the concentration of INH in rat plasma samples for 60 and 180 days, but also the concentration of Ac INH and INA in liver. Orange juice could reduce the m RNA expression of secretion transporters BCRP, ATP8B1 in duodenum and MRP4, MATE2-K in Kidney, and increase the protein expression of NAT2, FAAH1 and GLS2 in liver. INH could reduce the m RNA expression of secretion transporters BCRP in duodenum and MATE2-K in Kidney, and increase the MRP4 m RNA expression in Kidney. INH could increase the protein expression of FAAH1, GLS2, CYP2E1 and GST in liver.Conclusion:1. Orange juices could change the pharmacokinetic of INH in rats: no matter the time of orange juices drinking, it can increase the absorption and metabolic of INH. 2. The secretion transporters BCRP, ATP8B1 in duodenum and MRP4, MATE2-K in kidney may participate the transport of INH. 3. Orange juices will cause other drug-drug interactions by reduce the m RNA expression of secretion transporters BCRP, ATP8B1 in duodenum and MRP4, MATE2-K in Kidney.