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目的:比较研究BCRP基因多态性对瑞舒伐他汀单剂量和多剂量连续给药后人体药动学的影响。方法:筛选24例健康受试者,按BCRP 421 C>A基因型分组:421CC野生组(n=15)和421CA+AA突变组(n=9)。受试者每日口服规定剂量的瑞舒伐他汀,连续7 d;每日按规定时间点采集受试者血样和尿样;采用液相色谱-串联质谱联用法(HPLC-MS/MS)测定血浆和尿样中的瑞舒伐他汀浓度。结果:单剂量给药后,瑞舒伐他汀在BCRP 421CA+AA突变组的AUC0～t,C max和尿药排泄百分数Percent_excretion显著高于421CC野生型组(P=0.030,0.015和0.041),半衰期t1/2和达峰时间T max在两组人群中无差异(P>0.05)。与单剂量结果不同,多剂量连续给药达稳态后,稳态AUC ss,C max、总清除率CL total_ss/F和肾清除率CL R_ss在野生型组和突变组之间均无显著性差异(P>0.05),但半衰期t1/2在野生组显著延长[(14.1±3.1)vs(11.8±2.2)h,P=0.035],且野生组的蓄积比Rac也高于突变组(P=0.064)。结论:BCRP 421C>A基因多态性是影响瑞舒伐他汀人体药动学改变的重要因素。
OBJECTIVE: To compare the effects of BCRP gene polymorphism on pharmacokinetics of rosuvastatin after single and multiple doses of continuous administration. METHODS: Twenty-four healthy subjects were screened for the BCRP 421 C> A genotype: 421 CC wild-type (n = 15) and 421 CA + AA mutant (n = 9). Subjects received the prescribed daily dose of rosuvastatin orally for 7 consecutive days. Blood samples and urine samples of the subjects were collected daily at regular time points. Liquid chromatography-tandem mass spectrometry (HPLC-MS / MS) Rosuvastatin concentrations in plasma and urine samples. Results: After single-dose administration, the AUC0 ~ t, Cmax and urinary excretion percentage of rosuvastatin in BCRP 421CA + AA mutant group were significantly higher than those in 421CC wild-type group (P = 0.030, 0.015 and 0.041) t1 / 2 and peak time T max in the two groups of no difference (P> 0.05). In contrast to the single-dose results, steady-state AUC ss, C max, total clearance CL total_ss / F, and renal clearance CL R_ss did not differ between the wild-type group and the mutated group (P <0.05), but the half-life t1 / 2 in the wild-type group was significantly longer than that in the wild-type group [(14.1 ± 3.1) vs (11.8 ± 2.2) h, P = 0.035] = 0.064). Conclusion: The polymorphism of BCRP 421C> A gene is an important factor affecting the pharmacokinetics of rosuvastatin.