The Effect And Mechanism Of Capsaicin On Processes Of Disposition Of Irinotecan In Rats Based On Enzymes And Transporters

[OBJECTIVE]Investigate the effect of capsaicin(CAP) on pharmacokinetic of irinotecan(CPT-11) and its main metabolites in rats plasma from the whole animal level.Further clarify the mechanism that CAP affect distribution metabolic and excretion of CPT-11 in rats, involving several pathway. Multiple perspectives to investigate the regulatory mechanism of effect of CAP on CPT-11 in vivo ADME behavior changes at hepatic microsomes metabolism model- bile duct drainage model- the whole animal drug disposition model of three levels, based on enzymes and transporter mediated pathway. Build a scientific basis and guidance for the rational use of CPT-11, as well as enzymes metabolize drugs, provide ideas and learn to avoid adverse caused food-drug interactions.[METHODS]The studies established a LC-MS/MS method for determination of or the quantification of CPT-11, SN-38, SN-38 G and APC in rat plasma, bile, liver tissue and liver microsomes. We explored the effect of CAP on the pharmacokinetics of CPT-11 and its main metabolites. Then we investigated the variation of concentrations of irinotecan and its metabolites in the liver tissue and the effect of CAP on the activities of Ces2 and Ugt1a1. Finally, we investigated effect of CAP on the biliary excretion of CPT-11 and its main metabolites.[RESULTS]After 7 days of pretreatment with CAP at the dose of 3 or 8 mg?kg-1, the plasma concentration of SN-38 in CAP pretreatment groups was much higher than Nnormal group after injection of CPT-11. Upon seven consecutive days pretreatment with CAP,the AUC0-t and AUC0-? of SN-38 after administration were increased by 40%. All were significantly(P< 0.05) higher than the group pretreated with vehicle. However,there were no significant pharmacokinetic parameters differences of other analyte between CAP pretreatment groups and Nnormal group. The concentration of SN-38 in liver tissue was lower, compared to Normal control group at the 1, 2, 4 h points. The difference was not statistically significant. However, the concentration ratio of plasma and liver tissue samples were much higher in CAP pretreatment group, furthermore,the difference was statistically significant at the 2 h point(P<0.05). It was found that the IC50 of CAP for Ces2 and Ugt1a1 enzyme respectively were 60.74 ?M and 408.2?M by incubation experiments. The Ces2 enzyme activity in rat liver microsomes was declined, after 7 days of pretreatment with CAP. Besides, there were significant differences between Normal control group and CAP pretreatment groups at dose of 8mg·kg-1(P < 0.05). And the cumulative bile excretion of CPT-11 and its main metabolites between CAP group and Normal group was no significant differences.[CONCLUSION]In conclusion, CAP might inhibit the hepatic transporters Oatp1b2 of SN-38 uptake, resulting in variation of pharmacokinetics of SN-38. CAP also inhibited weakly the activity of Ces2. Finally, CAP significantly raised SN-38 in vivo exposure through the comprehensive effects of multi-pathway and multi-part. This study confirmed the effect of CAP on pharmacokinetics of SN-38, the active metabolite of CPT-11, in rats, illustrated the effect of CAP on key enzymes and transporters mediated pathway, and comprehensive explored the effect of CAP on distribution,metabolism and excretion of CPT-11. It built a scientific foundation and guidance for the rational use of CPT-11, as well as enzymes metabolize drugs, provided ideas and learn to avoid adverse caused food-drug interactions.