| ObjectiveCurcumin has numerous pharmacological values, but its very low bioavailability hinders the clinical utilization.Piperine was verified to enhance oral absorption of curcumin, while its mechanism remains controversial. Thus, to elucidate the mechanism of oral absorption of curcumin which is improve by piperine, the research is attempt to investigate the pharmacokinetic and pharmacodynamic Influence of piperine on curcumin as well as the influence of piperine on the protein expression of UGTs and SULTs, in order to offer experimental evidence for application of curcumin and piperine.Methods1. Pharmacokinetic Influence of piperine on curcumin in rat in vivoTo invetigate the pharmacokinetic Influence of different concentrations of piperine on curcumin in rats in vivo, the control group is administrated curcumin (200mg/kg) separately and the combination group is given by different concentration ratio of curcumin and piperine (1:1-100:1). Then, to testify the Influence of piperine on curcumin in rats in vivo in different time, the control group is administrated curcumin (200mg/kg) identically, while the combination of piperine and curcumin is administrated consistent concentration of piperine(10mg/kg) ahead of different time (0-8h). Verify plasma concentration of curcumin by adapting HPLC-MS/MS which was established, process data of plasma concentration with DAS2.0 pharmacological application and compared pharmacokinetic parameters between the groups respectively.2. Influence of piperine on protein expression of UGTs and SULTsIn order to find out the Influence of piperine on protein expression of UGTs and SULTs,the control group is administrated normally, while the other groups are given with piperine (lOmg/kg) in different time (0.5-8h). Then, test protein expression of UGT1A1, UGT1A6, UGT1A8, SULT1A1 and SULT1A3 in liver and ileum with Western Blot. Identically, detect the protein expression of UGT1A1, UGT1A6, UGT1A8, SULT1A1 and SULT1 A3 in cells with Western Blot via the different concentration of piperine (10-200μM) and differnt time (0.5-8h) in which the cells is pretreated. Compare data which is achieved from above between groups respectively.3. Influence of combination of curcunmin and piperine on blood lipid in hyperlipemia ratApart from the control group, the other treatment groups are intramuscularly injected with Triton WR-1339 to obtain the hyperlipemia model. Acquire the blood after being administrated in 7 days. Then, test content of TG, TC, HDL-C and LDL-C among the groups and compare data between the groups respectively.Results1. Pharmacokinetic Influence of pipeline on curcumin in rat in vivoDemonstrated by experimental results of different concentration of combination of curcumin and piperine via lavage administration, area under the curve (AUCo-t) and maximum concentration (Cmax) were significantly enhanced when the ratio of concentration between curcumin and piperine was 20:1 compared with the separate treatment group, it was 167% and 129% respectively, while clearance (CL) reduced 61%. The Tmax and half-life (ti/2) performed slightly.Revealed from the experimental results of diverse time differences of curcumin and piperine in lavage administration, compared with the alone treatment, AUCo-twas elevated 275%-597%(P＜0.01 or P<0.05) when the piperine was pre-treated 0.5-8h. Additionally, rats pretreated with PIP for 6 h achieved significant increase in Cmax and AUC0-t (342.93±31.89μg/L,228.67±60.87μg/L-h), which was 609% and 597% (P＜0.01). Other pharmacokenetic parameters, such as CL, Vd and t1/2a, differed slightly.2. Influence of piperine on protein expression of UGTs and SULTsManifested by experimental results, in rats liver, piperine acquired the significant inhibition on UGT1A6, UGT1A8 and SULT1A1 in 6h (P＜0.01 or P<0.05). Additionally, the inhibition of piperine on UGT1A1, SULT1A1 and SULT1A3 was significant in rats intestine when piperine was pre-treated for 6h and 8h (P＜0.01), the inhibition was strong on UGT1A6 when piperine was pre-treated for 6h (P＜0.05).Within the different concentration of piperine was administrated in cell experiment, it was shown that piperine had inhibitory efficacy on UGTs and SULTs in HepG2 cells. Identically, it had inhibitory efficacy on UGT1A1, UGT1A8 and SULT1A1 (P＜0.01 or P<0.05). It was found out that piperine achieved the most significant inhibition on UGT1A8 and SULT1A1 in 6h (P<0.01) in HepG2 cells. Additionally, it appeared evident inhibition on UGTA1A1, UGT1A6, UGT1A8 and SULT1A1 when piperine was given for 6h and 8h in Caco-2 cells (P<0.01 or P<0.05).3. Influence of combination of curcumin and piperine on blood lipid in hyperlipemia ratIllustrated by the results of research, after intramuscular injection of Triton WR-1339, the content of TC, TG and LDL-C were significantly increased (P＜0.01) in the serum of model group, compared with the control group. In addition, content of TC and TG were reduced evidently in the serum of both fenofibrate and piperine groups which is pre-treat 4h and 6h, compared with the model control group (P＜0.01). Identically, the content of LDL-C was reduced apparently in all treatment groups except only dose curcumin (P＜0.01 or P<0.05). Compared with the curcumin group and combination with piperine group, the concentration of TC, TG in piperine pre-4 h and 6 h group were decreased (P< 0.01).ConclusionsThe oral bioavailability and antilipemic effect of curcumin can be enhanced by piperine which is preprocessed in different time. Identically, piperine has tissue specificity and isoform specificity on the expression of UGTs and SULTs, which can offer numerous experimental basis for absorption mechanism of curcumin enhanced by piperine, in order to instruct the clinical medicine usage and improve the utilization of drug. |
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