Effect Of Concomitantly Administered Curcumin On The Pharmacokinetics Of Talinolol In Healthy Chinese Subjects

OBJECTIVESTo study the pharmacokinetics of talinolol,evaluate the effect of concomitantly administered low and high dose of Chinese herbal medicine curcumin on the oral pharmacokinetics of the nonmetabolized and p-glycoprotein-transported drug talinolol in humans,and to assess the potential impact of curcumin administration on luminal p-gp and other uptake transporters like OATP,and discuss the influence of these transporters on the disposition of talinolol in human subjects.METHODS1.Dose administrationThe study was conducted in a self-controlled three-period experiment in a randomized,open-labeled design in 12 healthy Chinese volunteers with a wash out period of 1 week among the administration of a single oral dose of 50 mg talinolol,the consecutive 6-day administration of curcumin(300 mg/day)and concomitant administration of a single oral dose of 50 mg talinolol,and the consecutive 6-day administration of curcumin(600 mg/day)and concomitant administration of a single oral dose of 50 mg talinolol on the seventh day.The wash-out period was one week.2.Biology samples collection and analysis2.1 Serial blood samples were collected from an in-dwelling venous catheter(anticoagulated with sodium heparin)at 0,0.5,1,1.5,2,3,4,6,8, 12,24,36,48 and 60h before and after talinolol administration.Blood samples were collected in plastic containers,and immediately centrifuged. The separated plasma samples were immediately frozen at -80℃until assayed.2.2 Concentrations of talinolol were measured in plasma by HPLC-MS/ESI.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 40,80,120 and 180 min after talinolol administration.RESULTS1.Determination of talinololThe average extraction recoveries for talinolol were above 83%.The methodology recoveries were between 101%and 102%.The limit of detection(LOD)was 0.3 ng·mL^-1.The calibration curve was linear in the range of 1.0～800.0 ng·mL^-1for talinolol.The intra-day and inter-day RSD were less than 8%,the stability test showed that the plasma samples of talinolol were all stable under different conditions(RSD＜10%).2.Pharmacokinetics of talinololThe mean pharmacokinetic parameters after a single oral administration of 50mg talinolol are as follows:t_maxare 2.0±0.7 h,t_1/2are 12.0±2.6 h,C_maxare 147.8±63.8 ng·mL^-1,AUC_0-60are 1763.7±377.5 ng·h·mL^-1,AUC_0-∞are 1860.0±377.9 ng·h·mL^-1and CL/F are 27.9±5.5 L·h^-1,respectively.3.The effect of concomitant curcumin on the pharmacokinetics of talinololConsecutive 6-day administration of low and high dose curcumin significantly decreased the AUC of talinolol,and the CL/F was increased significantly;Compared woth control,consumption of low dose curcumin for 6 days reduced the AUC_0-∞of talinolol by 33%(P =.001)and the CL/F was increased by 54%(P =.003),consumption of high dose curcumin for 6 days reduced the AUC_0-∞of talinolol by 18%(P=.03)and the CL/F was increased by 32%(P =.045),C_max,t_maxand t_1/2values of talinolol were not significantly affected by concomitant low or high dose curcumin.There was no significant difference in talinolol pharmacokinetics after low dose compared with high dose curcumin.The interindividual variability in AUC_0-60and C_maxof talinolol was comparable in three study periods;the C.V.of AUC_0-60and C_maxwere 26%and 40%after 300mg/day curcumin,24%and 36%after 600mg/day curcumin,and 21%and 43%after talinolol alone,respectively.4.Adverse effect assessmentNo clinically significant effects on blood pressure and heart rates were observed after administration of talinolol alone or after concomitant curcumin.DISCUSSIONS AND CONCLUSIONS1.The pharmacokinetics of talinolol in Chinese healthy volunteers was similar as reported by foreign literatures.2.Because both low and high dose curcumin lowered rather than increased the AUC of talinolol,our findings suggest:2.1.Curcumin preferentially inhibited an intestinal uptake process like organic anion transporting polypeptide family OATP rather than p-glycoprotein;2.2.Upregulation of other effiux transporters like multi-drug related protein-2(MRP-2)may be promoted by curcumin;2.3.Long-term administration of curcumin may upregulate the expression of intestinal p-glycoprotein and MDR1 gene;2.4.Low intraluminal curcumin concentration due to too low dose consumed or extensive metabolism by CYP1A may result in attenuated effect of curcumin on p-glycoprotein.