Effect Of Piperine On The Pharmacokinetics Of Curcumin In Healthy Chinese Volunteers

OBJECTIVESTo study the pharmacokinetics of curcumin and piperine, evaluate the effect of concomitantly administered single- and multi-dose of piperine on the oral pharmacokinetics of curcumin in humans, and help to formulate optimum dosages and make for clinic therapeutics.METHODS1. Dose administrationParticipants were assigned by means of a permuted block randomization algorithm into one of three groups. Each group completed three visits. The volunteers were randomized to receive seven days of placebo daily (visit A and B),20 mg of piperine daily (visit C). After seven days, the single-dose pharmacokinetics of an 600-mg dose of curcumin(visits A) or piperine 20 mg administered in combination with 600 mg of curcumin(visit B and C) was evaluated. Each visit was separated by at least a two-week washout period to allow for the elimination of piperine and to avoid treatment-by-period interactions. 2. Biology samples collection and analysis2.1 Serial blood samples were collected from an in-dwelling venous catheter (anticoagulated with sodium heparin) at 0,0.25,0.5,1,2,4,6,8, 12,24,36,48 and 60 h before and after curcumin administration. Blood samples were collected in plastic containers, and immediately centrifuged. The separated plasma samples were immediately frozen at-70℃until assayed.2.2 Concentrations of curcumin and piperine were determined in plasma by HPLC-ESI-MS/MS.3. Safety monitoringAdverse event was elicited from the volunteers by means of spontaneous report and specific questioning. Serial measurements of blood pressure, heart rate, and ECG were recorded 40,90,140 and 200 min after curcumin administration.RESULTS1. Determination of curcumin and piperine The calibration curve were linear in the range of 1.00-100.00 ng.mL-1 for curcumin and 0.50-800.00 ng.mL"1 for piperine. The limit of detection (LOD) were 0.50 ng.mL-1 and 0.10 ng·mL-1, respectively. The average extraction recoveries for curcumin and piperine were above 85.63%. The methodology recoveries were between 94.20%and 108.36 %. The intra-day and inter-day RSD were less than 12.36%, the stability test showed that the plasma samples of curcumin and piperine were all stable under different conditions(RSD<7.77%).2. Pharmacokinetics of curcumin and piperineThe mean pharmacokinetic parameters after a single oral coadministration of 20mg of piperine and 600 mg of curcumin viz. AUC0-60h, AUC0-∞, Cmax, tmax, t1/2, CL/F and MRT were 549.17±272.49 ng-h/ml, 568.66±274.03 ng-h/ml, 30.34±14.06 ng/ml, 6.13±2.30 h, 13.26±5.09 h,1352.95±781.44 mL/h and 26.64±7.95 h for curcumin and 5642.20±956.03 ng-h/ml,5932.26±1082.01 ng-h/ml,290.00±42.47 ng/ml, 3.50±1.78 h,13.26±1.91 h,974.28±507.02 mL/h and 22.83±7.65 h for piperine, respectively.3. The effect of concomitant piperine on the pharmacokinetics of curcuminCompared with control, consumption of single-dose of piperine increased the AUC0-60h of curcumin by 17%, the tmax and t1/2 was prolonged by 44% and 47, respectively, and the CL/F was decreased by 33%. Consumption of multi-dose of piperine increased the AUC0-60hand Cmax of curcumin by 65% and 42%, respectively; the tmax and t1/2 was prolonged by 80% and 55%, respectively, and the CL/F was decreased by 51%. The clinical significance was considerable though there was no significant difference of these values among the three phases.4. Adverse effect assessmentNo clinically significant effects on blood pressure and heart rates were observed after administration of curcumin alone or after concomitant piperine.CONCLUSIONS1. This paper report the pharmacokinetics of piperine in Chinese healthy volunteers for the first time. The bioavailability of curcumin is low and the pharmacokinetic parameters of curcumin was found extremely variable. Orally administered curcuminoids are absorbed from the alimentary tract and present in the general blood circulation after largely being metabolized to the form of glucuronide conjugates.2. Coadministration of single- and multi-dose of piperine increased the AUC of curcumin in different degrees and the elimination was also slowed down with predominant clinical significance especially with multible dose and long term studies of piperine.