Zhou Q, Ruan Z-r, Yuan H, Zeng S
Department of Pharmacy, the 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, Zhejiang Province, China.
Arzneimittelforschung. 2012 Nov;62(11):519-24. doi: 10.1055/s-0032-1323696. Epub 2012 Aug 31.
To evaluate the impact of single-nucleotide polymorphisms (SNPs) in CYP2C9, MDR1, SLCO1B1 and ABCG2 on the pharmacokinetics of fluvastatin in Chinese participants.A pharmacokinetic study of fluvastatin (single dose 40 mg) was conducted in 12 healthy Chinese volunteers. Plasma concentrations of fluvastatin were determined by a high-performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters were calculated by non-compartmental method. The SNPs were determined by TaqMan®(MGB) genotyping assay.Effect of CYP2C93 (c.1075A>C) on area under the plasma concentration-time curve (AUC) of fluvastatin was statistically significant. Heterozygous variant (C/A) carriers had higher AUC values compared to homozygous wild type (A/A) carriers (922.03±148.17 µg · h · L - 1 vs. 496.00±168.93 µg · h · L - 1, P=0.003092). The elimination half-life (T 1/2) values of fluvastatin were longer in MDR1 2677non-G carriers than in MDR1 2677G carriers (2.21±0.47 h vs. 1.25±0.62 h, P=0.02319), and also they were longer in MDR1 1236T-2677non-G-3435T carriers than in MDR1 1236C-2677G-3435C carriers (2.31±0.51 h vs. 1.32±0.62 h, P=0.03320). MDR1 C3435T polymorphism had a significant effect on maximal plasma concentrations (C max) of fluvastatin. Mutation gene T (TT+CT) carriers had higher C max values compared to homozygous wild type (C/C) carriers (688.54±142.67 µg · L - 1 vs. . 413.78±177.83 µg · L - 1, P=0.01448). Some SNPs such as MDR1 C1236T, ABCG2 c.34G>A, ABCG2 c.421C>A, SLCO1B1 c.388 A>G, SLCO1B1 c.521 T>C, SLCO1B1 c.571 T>C and SLCO1B1 c.597 C>T have no significant effects on fluvastatin pharmacokinetics.CYP2C93(1075A>C), MDR1 C3435T and MDR1 G2677T/A were determinants of inter-subject variability in fluvastatin pharmacokinetics in healthy Chinese volunteers.
评估细胞色素P450 2C9（CYP2C9）、多药耐药蛋白1（MDR1）、有机阴离子转运多肽1B1（SLCO1B1）和ATP结合盒转运体G2（ABCG2）中的单核苷酸多态性（SNP）对氟伐他汀在中国受试者体内药代动力学的影响。对12名健康中国志愿者进行了氟伐他汀（单剂量40mg）的药代动力学研究。采用高效液相色谱-荧光检测法测定血浆中氟伐他汀的浓度。采用非房室模型方法计算药代动力学参数。通过TaqMan®（MGB）基因分型检测法测定SNP。CYP2C93（c.1075A>C）对氟伐他汀血浆浓度-时间曲线下面积（AUC）的影响具有统计学意义。与纯合野生型（A/A）携带者相比，杂合变异型（C/A）携带者的AUC值更高（922.03±148.17µg·h·L⁻¹ 对496.00±168.93µg·h·L⁻¹，P=0.003092）。MDR1 2677非G携带者中氟伐他汀的消除半衰期（T₁/₂）值长于MDR1 2677G携带者（2.21±0.47h对1.25±0.62h，P=0.023从），MDR1 1236T-2677非G-3从5T携带者中氟伐他汀的消除半衰期也长于MDR1 1236C-2677G-3从5C携带者（2.31±0.51h对1.32±0.62h，P=0.03320）。MDR1 C3从5T多态性对氟伐他汀的最大血浆浓度（Cmax）有显著影响。与纯合野生型（C/C）携带者相比，突变基因T（TT+CT）携带者的Cmax值更高（688.54±142.67µg·L⁻¹对413.78±177.83µg·L⁻¹，P=0.01448）。一些SNP，如MDR1 C1236T、ABCG2 c.3从G>A、ABCG2 c.421C>A、SLCO1B1 c.388 A>G、SLCO1B1 c.521 T>C、SLCO1B1 c.571 T>C和SLCO1B1 c.597 C>T对氟伐他汀的药代动力学无显著影响。CYP2C93（1075A>C）、MDR1 C3从5T和MDR1 G2677T/A是健康中国志愿者中氟伐他汀药代动力学个体间差异的决定因素。
