Different effects of the ABCG2 c.421C>A SNP on the pharmacokinetics of fluvastatin, pravastatin and simastatin
Different effects of the ABCG2 c.421C>A SNP on the pharmacokinetics of fluvastatin, pravastatin and simastatin
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DOI：
10.2217/pgs.09.85
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发表时间：
2009-10-01
期刊：
影响因子：
2.1
通讯作者：
Niemi, Mikko
中科院分区：
文献类型：
--
作者：
Keskitalo, Jenni E.;Pasanen, Marja K.;Niemi, Mikko
目的：本研究旨在研究ABCG 2 c.421C>A（p.Gln141Lys; rs 2231142）基因型对氟伐他汀、普伐他汀和辛伐他汀药代动力学的可能影响。材料和方法：在一项交叉研究中，5名ABCG 2 c.421A/A基因型健康志愿者、4名c.421C/A基因型健康志愿者和23名c.421C/C基因型健康志愿者单次摄入40 mg剂量的氟伐他汀、普伐他汀和辛伐他汀，洗脱期为1周。测量血浆他汀类药物浓度达12 h。结果如下：A/A基因型受试者从0 h至无穷大的氟伐他汀血药浓度-时间曲线下面积（AUC（0-无穷大））的估计值比C/A或C/C基因型受试者大97%（p = 0.015）或72%（p = 0.009）。A/A基因型受试者辛伐他汀内酯的AUC（0-无穷大）比C/C基因型受试者大111%（p = 0.005）。A/A基因型个体的辛伐他汀酸：内酯AUC（0-无穷大）比C/C基因型个体小46%（p = 0.017）。ABCG 2基因型对辛伐他汀酸或普伐他汀的药代动力学没有显著影响。结论：ABCG 2基因的遗传变异显著影响氟伐他汀和辛伐他汀内酯的药代动力学，但对普伐他汀或活性辛伐他汀酸没有显著影响。在为个体患者选择他汀类药物及其剂量时，除了SLCO 1B 1和ABCB 1多态性外，ABCG 2基因分型也有助于预测他汀类药物的药代动力学。
Aims: This study aimed to investigate possible effects of the ABCG2 c.421C>A (p.Gln141Lys; rs2231142) genotype on fluvastatin, pravastatin and simvastatin pharmacokinetics. Materials & methods: In a crossover study, five healthy volunteers with the ABCG2 c.421A/A genotype, four with the c.421C/A genotype and 23 with the c.421C/C genotype ingested a single 40-mg dose of fluvastatin, pravastatin and simvastatin, with a washout period of 1 week. Plasma statin concentrations were measured up to 12 h. Results: The estimated marginal mean area under the plasma concentration-time curve from 0 h to infinity (AUC(0-infinity)) of fluvastatin was 97% (p = 0.015) or 72% (p = 0.009) larger in participants with the A/A genotype than in those with the C/A or C/C genotype. The AUC(0-infinity) of simvastatin lactone was 111% (p = 0.005) larger in participants with the A/A genotype than in participants with the C/C genotype. The simvastatin acid:lactone AUC(0-infinity) ratio was 46% (p = 0.017) smaller in individuals with the A/A genotype than in those with the C/C genotype. The ABCG2 genotype had no significant effect on simvastatin acid or pravastatin pharmacokinetics. Conclusions: Genetic variability in ABCG2 markedly affects the pharmacokinetics of fluvastatin and simvastatin lactone, but has no significant effect on pravastatin or active simvastatin acid. Genotyping for ABCG2 in addition to SLCO1B1 and ABCB1 polymorphisms could help in predicting statin pharmacokinetics when selecting a statin and its dose for an individual patient.