Influence Of NTCP 800C＞T Polymorphism On Pharmacokinetics Of Rosuvastatin In Chinese Healthy Males

AIMS: To investigate the allele frequence of NTCP 800C＞T inChinese healthy Han population, and then determine the influence ofNTCP 800C＞T polymorphism on pharmacokinetics of rosuvastatin inChinese healthy males.METHODS: Polymerase chain reaction-restriction fragment lengthpolymorphism (PCR-RFLP) was employed in NTCP 800C＞T, OATP1B1521T＞C and CYP2C9*3 genotype analysis. Twelve healthy males whoare OATP1B1 521TT and CYP2C9*1/*1 wild-type homozygotes wereselected to participate in this study. Six were NTCP 800CC wild-type, theothers were carriers with least one 800C＞T mutant allele(five subjectshad a genotype of 800CT and one was homozygotes of 800TT). Eachwas given a single oral dose of 10mg rosuvastatin after a overnight fast,the blood samples were drawn at 0,0.5,1,1.5,2,3,4,5,6,8,10,12,24,48 and 72 hours after drug administration. The plasmaconcentrations of rosuvastatin were measured by HPLC-MS method.Pharmacokinetic parameters were compared between different NTCP800C＞T gentotypes.RESULTS: 140 healthy male volunteers were genotyped for NTCP800C＞T polymorphism. The frequencies of NTCP 800C and NTCP800T were 93.9% and 6.1%, respectively. The allele frequencieswere in Hardy-Weinberg equilibrium. The pharmacokinrtics parametersof rosuvastatin showed a significant differencese between the twogenotype groups. The mean AUC_0-72 and AUC_0-∝of rosuvastatin werehigher in NTCP 800CT+TT group than in the NTCP 800CCgroup(183.91±72.83vs.103.83±28.15ng.h/mL, P＜0.05; 219.98±98.56VS.113.43±33.73ng.h/mL, P＜0.05). The Cmax value was 2.5 fold higherin the 800CT+TT group than in the NTCP 800CCgroup(22.00±8.53ng/mL vs. 8.57±3.00ng/mL, P＜0.05). The tmax valuewas shorter in NTCP 800CT+TT group than in NTCP 800CCgroup(2.3 hours vs. 4.0 hours, P＜0.05). As for oral clearance, NTCP800CC group was higher than in NTCP 800CT+TT group(93.22±20.76L/h VS.55.98±29.96L/h, P＜0.05). The t_1/2 valueshowed no difference between these two groups.CONCLUSIONS: The NTCP 800C＞T variant is relatively commonin Chinese population,which frequency is 6.1% and consistented with theresults calculated from the direct sequencing in American Aisans. TheNTCP 800C＞T polymorphism may play an important role in thepharmacokinetics of rosuvastatin in Chinese healthy males after theexclusion of impact of OATP1B1 and CYP2C9 genetic polymorphism.