Effect Of OATP1B1 388G→A Heterogenesis On Pharmacokinetic Characterstics Of Pitavastatin In Chinese Volunteers

Background Pitavastatin , a novel statin, which is mainly transited into liver cells by OATP1B1 and then is metabolized and eliminated. OATP1B1, which plays an important role in drug uptaking in the liver is a type of specific transport protein of liver and has many substrates. Genetic polymorphism of OATP1B1 is a main reason of differences of metabolism among individuals after intaking drugs, but it dosen't know if OATP1B1 mutation affects disposition of pitavastatin in vivo. Therefore, studying the effect of OATP1B1 polymorphism on the pharmacokinetic of pitavastatin has an important significance to the clinical application of it.Objectives To study the effect of OATP1B1 common gene mutation 388G→A in Chinese human on the pharmacokinetics of pitavastatin and instruct the reasonable clinical application of pitavastatin .Methods1 Determination of pitavastatin in plasm was established with LC-MS and method was put into consideration based on demanding of analysis of biology sample.2 30 volunteers were selected and collected 2 mL blood in order to made genotyping of OATP1B1 with the method of polymerase chain reaction - restriction fragment length polymorphism and distinguished 388G→A heterogenesis and wild type homozygote (non-mutant), and 9 subjects of 388G→A heterogenesis and 6 subjects of wild type homozygote were selected to involve in pitavastatin pharmacokinetic test.3 With 3×3 Latin square design, the mutant and wild type homozygote subjects were applied chiasmaticly with single oral dose, 1, 2 and 4 mg pitavastatin calcium tablets and collected 5 mL blood at 0, 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0, 36.0, 48.0h , which were centrifugalized and obtained blood plasma, and then were kept frozen at-20℃.4 According to the measured data of concentrations of plasma, the main pharmacok- inetic parameters of pitavastatin were calcuLated by DAS2.0 software , the main pharmacokinetic parameters of OATP1B1 mutation group and OATP1B1 wild type homozygote group were analysed and compared.Results1 The determination of pitavastatin in plasm with LC-MS has good sensitivity and specificity and consistented with demanding of analysis of biology sample.2 Genotyping of OATP1B1 388G→A mutant was made with the method of polymerase chain reaction - restriction fragment length polymorphism and showed that there were 21 subjects with 388G→A mutant, accounting to 70% of total and wild type homozygote accounted to 30% .3 During the dose of 1-4mg pitavastatin,the main pharmacokinetic parameters of 388G→Aheterogenesis subjects and wild type homozygote subjects both consistented with linear relationship, heterogenesis subjects'and wild type homozygote subjects'pharmacokinetic parameters of Cmax,AUC0-48,AUC0-∞were both notable higher as increasing of dose and both had linear relationship between pharmacokinetic parameters and dose, and the coefficient correlation were 0.9725, 0.9989; 0.989, 0.9897; 0.9936, 0.9877.This indicates that clinical application is possible in the oral dose of 1-4mg.4 We found that there were significant differences between OATP1B1 common mutation in the 388G→A and wild type homozygote for pitavastatin pharmacokinetic process. The main pharmacokinetic parameters of Cmax,AUC0-48,AUC0-∞of OATP1B1 common mutation in the 388 G→A had notable higher than wild type homozygote at dose of 1, 2, 4mg, but the parameter of Cl/F was lower: After single oral pitavastatin 1mg ,the Cmax , AUC0-48 , AUC0-∞, Cl/F parameters of OATP1B1 common mutation in the 388 G→A and wild type homozygote were 27.23±5.73,12.23±1.58ng·mL^-1,p=0.000; 117.12±36.94,55.86±18.9 ng·h·mL^-1,P=0.003; 126.74±44.05,60.64±18.63 ng·h·mL^-1 P=0.002; 8.78±2.99, 17.54±4.21 L·h^-1,P=0.000; After single oral pitavastatin 2mg,the Cmax , AUC0-48 , AUC0-∞, Cl/F parameters of OATP1B1 common mutation in the 388 G→A and wild type homozygote were 39.22±8.45, 22.897±4.03ng·mL^-1, P=0.000; 182.19±86.46, 100.422±21.194 ng·h·mL^-1, P=0.024; 199.64±98.70, 108.116±24.94 ng·h·mL^-1, P=0.026; 12.46±4.79,19.21±3.74L·h^-1, P=0.012; After single oral pitavastatin 4mg, the Cmax , AUC0-48 , AUC0-∞, Cl/F parameters of OATP1B1 common mutation in the 388 G→A and wild type homozygote were 94.92±13.41, 47.41±11.23ng·mL^-1, P=0.000; 392.12±129.66, 241.63±58.3 ng·h·mL^-1, P=0.011; 406.91±138.94, 266.12±65.48ng·h·mL^-1, P=0.022; 10.98±3.97, 15.73±3.93L·h^-1, P=0.032.But the parameters of Ka, Ke , t1/2, Tmax had no differences.Conclusions OATP1B1 388G→A mutated would obviously affect the pharmacokinetic characterstics of pitavastatin in Chinese healthy subjects and the study showed that the absorption degree in mutated group was significantly greater than in wild type homozygote group, but the elimination process was significantly lower in the former than in the latter.