title: The effect of Na+/taurocholate cotransporting polypeptide (NTCP) c.800C > T polymorphism on rosuvastatin pharmacokinetics in Chinese healthy males.
abstract: This study was designed to investigate the potential association between NTCP c.800C >T polymorphism and rosuvastatin pharmacokinetics in Chinese healthy males. 305 individuals were enrolled to identify NTCP c.800C > T, OATP1B1 c.521T > C and BCRP c.421C > A genotypes by direct sequencing and pyrosequencing methods, respectively. 17 healthy volunteers who were OATP1B1 c.521TT and BCRP c.421CC wild-type homozygotes with different NTCP c.800C > T genotype were selected to participate in this pharmacokinetic study. Nine were NTCP c.800CC wild-type homozygotes and the other eight subjects were carriers with at least one c.800T variant allele (seven subjects with c.800CT genotype and one was homozygote of c.800TT). All the subjects received a single oral dose of 10 mg rosuvastatin. The plasma concentrations of rosuvastatin were measured up to 72 h by a LC-MS method. NTCP c.800C > T genetic polymorphism markedly effected rosuvastatin pharmacokinetics. The AUC(o-72) and AUC(0 --> ∞) in subjects with NTCP c.800CT + TT genotype were 56% (162.64 ± 37.55 vs. 103.99 ± 28.15 ng x h/ml, P = 0.016) and 57% greater (178.51 ± 42.75 vs. 113.60 ± 33.73 ng x h/ml, P = 0.020) than those in the c.800CC wild-type subjects, respectively. In the c.800CT + TT mutant group, the C(max) was about 78% higher than those in c.800CC genotype (14.31 ± 3.63 vs. 8.04 ± 1.72 ng x h/ml, P = 0.004). The oral clearance (CL/F) of rosuvastatin in subjects with the c.800CT+TT genotype was only 63% of those in the c.800CC genotype (58.32 ± 12.16 vs. 93.04 ± 20.61 ng x h/ml, P = 0.009). The half-time (T1/2) and the T(max) had no significant difference between two groups (p = 0.466 and 0.713, respectively). NTCP c.800C > T polymorphism play a critical role in the individual variability of rosuvastatin pharmacokinetics in Chinese healthy males after excluding the impact of OATP1B1 c.521T > C and BCRP c.421C > A polymorphisms.
authors.forename: Xiao-Ya
authors.initials: XY
authors.lastname: Lou
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Guo
authors.initials: G
authors.lastname: Wang
authors.forename: Dong-Li
authors.initials: DL
authors.lastname: Hu
authors.forename: Dong
authors.initials: D
authors.lastname: Guo
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Tan
authors.forename: Hong-Hao
authors.initials: HH
authors.lastname: Zhou
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.forename: Hei-Hua
authors.initials: HH
authors.lastname: Bao
mesh_terms: D000328:Adult; D019540:Area Under Curve; D044466:Asian People; D002681:China / Q000453:epidemiology; D005464:Fluorobenzenes / Q000493:pharmacokinetics*; D005787:Gene Frequency; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D008297:Male; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D011743:Pyrimidines / Q000493:pharmacokinetics*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000493:pharmacokinetics*; D027981:Symporters / Q000235:genetics*
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D029363:Organic Anion Transporters, Sodium-Dependent; D011743:Pyrimidines; D013449:Sulfonamides; D027981:Symporters; C071908:sodium-bile acid cotransporter; D000068718:Rosuvastatin Calcium