| Objective:1. To study pharmacokinetics of rosuvastatin in Chinese healthy volunteers.2. To investigate the drug interaction of rosuvastatin and repaglinide on pharmacokinetics in rats.3. To study the drug interaction of rosuvastatin and repaglinide on drug concentration in rat liver.4. To investigate the drug interaction of rosuvastatin and repaglinide on rat plasma protein binding rate.Methods:1.20healthy male volunteers were administered single oral dose of rosuvastatin calcium tablets10mg. Blood samples were obtained and a validated LC-MS/MS method was used to determine rosuvastatin levels. Drug and Statistics (DAS, version2.0) was used to fit the non-compartmental model of rosuvastatin in human and to calculate its main pharmacokinetic parameters.2.(1) To study the effect of repaglinide on the pharmacokinetics of rosuvastatin: Twenty four wistar rats were randomly divided into four groups, and pretreated with water or0.5,1,2mg/kg repaglinide for seven days, then orally given10mg/kg of rosuvastatin. Blood samples were collected at0,0.25,0.5,1,2,3,4,6,8,12and24h. After disposition of plasma samples, rosuvastatin was determined in the established LC-MS/MS method, and main pharmacokinetic parameters were calculated by DAS2.0and statistically analyzed.(2) To study the effect of rosuvastatin on the pharmacokinetics of repaglinide:Twenty four wistar rats were randomly divided into four groups, and pretreated with water or5,10,20mg/kg rosuvastatin for seven days, then orally given1mg/kg of repaglinide. Blood samples were collected at0,0.083,0.25,0.5,1,2,3,4,6,8and12h. After disposition of plasma samples, repaglinide was determined in the established LC-MS/MS method, and main pharmacokinetic parameters were calculated by DAS2.0and statistically analyzed.3.(1) To study the effect of repaglinide on the concentration of rosuvastatin in liver: Twenty four wistar rats were randomly divided into four groups, and pretreated with water or0.5,1,2mg/kg repaglinide for seven days, then orally given10mg/kg of rosuvastatin, and liver samples were collected at1h. After disposition of liver samples, rosuvastatin was determined in the established LC-MS/MS method.(2) To study the effect of rosuvastatin on the concentration of repaglinide in liver:Twenty four wistar rats were randomly divided into four groups, and pretreated with water or5,10,20mg/kg rosuvastatin for seven days, then orally given1mg/kg of repaglinide, and liver samples were collected at1h. After disposition of liver samples, repaglinide was determined in the established LC-MS/MS method.4. The equilibrium dialysis combined with LC-MS/MS was used to determine the plasma protein binding rate of rosuvastatin and repaglinide and investigate the drug interaction.Results:1. The main pharmacokinetic parameters of rosuvastatin:t1/2(16.74±12.70)h,Tmax (2.50±0.61)h, Cmax (16.53±7.20) ng/mL, AUC0-72(91.89±44.34) ng/mL-h, AUC0-∞(95.24±45.65) ng/mL-h. The big individual differences of pharmacokinetic parameters may be due to the gene polymorphis of organic anion transporting polypeptide1B1(OATP1B1).2. In0.5mg/kg,1mg/kg and2mg/kg repaglinide plus rosuvastatin groups, AUC0-24of rosuvastatin was44.92%(p<0.01),72.28%(p<0.01),319.12%(p<0.01) more than that in water plus rosuvastatin group and Cmax was88.97%(p<0.01),141.79%(p<0.01),529.63%(p<0.01) more than that in water plus rosuvastatin group, while CLz were33.05%(p<0.01),43.07%(p<0.01),76.01%(p<0.01) less than that in water plus rosuvastatin group, respectively.In5mg/kg,10mg/kg and20mg/kg rosuvastatin plus repaglinide groups, Cmax of repaglinide was39.95%(p<0.05),47.88%(p<0.01),149.19%(p<0.01) more than that in water plus repaglinide group. In20mg/kg rosuvastatin plus repaglinide groups, AUC0-12of repaglinide was86.08%(p<0.05) more than that in control group, while CLz were46.64%(p<0.01) less than that incontrol group.3. In0.5mg/kg,1mg/kg and2mg/kg repaglinide plus rosuvastatin groups, the concentration of rosuvastatin in rat liver was24.87%(p<0.01),27.51%(p<0.01),49.57%(p<0.01) less than that of control group, respectively.In5mg/kg,10mg/kg and20mg/kg rosuvastatin plus repaglinide groups, the concentration of repaglinide in rat liver was24.72%(p<0.01),46.02%(p<0.01),63.35%(p<0.01) less than that of control group, respectively.4. In0.5mg/kg,1mg/kg and2mg/kg repaglinide plus rosuvastatin groups, plasma protein binding rate of rosuvastatin was0.98%,2.68%,4.21%less than that of control group. In5mg/kg and10mg/kg rosuvastatin plus repaglinide groups, plasma protein binding rate of repaglinide was1.17%and5.12%less than that of control group. All of those were statistically insignificant (p>0.05). Only in20mg/kg rosuvastatin group, plasma protein binding rate of repaglinide decreased by7.32%(p<0.05).Conclusions:The pharmacokinetic parameters of rosuvstatin varied widely between individuals, which may be due to the gene polymorphis of organic anion transporting polypeptide1B1(OATP1B1). The homology between rat oatplb2and human OATP1B1was discovered, and they played a same role during the process of transport. As the two substrates of OATP1B1(oatp1b2), rosuvstatin and repaglinide affect each other, resulting in increased AUC, Cmax and concentration in liver. Plasma protein binding ratio was not affected by each other. |
PDF Full Text Request