Cardiovascular Research Institute, University of California, San Francisco, California, USA.
Pharmacogenet Genomics. 2013 Jul;23(7):355-64. doi: 10.1097/FPC.0b013e3283620c3b.
Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of cerivastatin.
This study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1.
The resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B114 and OATP1B115 haplotype were associated with a significant reduction (P<0.001) in cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of cerivastatin.
Reduced function of OATP1B1 related to genetic variation and drug-drug interactions likely contributed to cerivastatin-induced rhabdomyolysis. Although cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1.
药物代谢酶和膜转运体的遗传变异以及伴随的药物治疗可以调节药物的有益和有害作用。我们研究了服用西立伐他汀后发生横纹肌溶解的患者是否在 SLCO1B1 中具有功能性遗传变异，以及他们是否同时服用了抑制 OATP1B1 的药物，导致西立伐他汀的积累。
本研究包括三个部分：（a）对 122 名服用西立伐他汀后发生横纹肌溶解的患者进行 SLCO1B1 基因重测序；（b）在稳定转染 pcDNA5/FRT 空载体、SLCO1B1 参考、变体和单倍型的 HEK293/FRT 细胞中，对鉴定的 SLCO1B1 非同义变体和单倍型进行功能评估；（c）在稳定转染参考 SLCO1B1 的 HEK293/FRT 细胞中，体外筛选横纹肌溶解病例中常用的 15 种药物对 OATP1B1 介导的西立伐他汀摄取的抑制作用。
SLCO1B1 基因的重测序鉴定了 54 个变体。SLCO1B1 非同义变体和单倍型的体外功能分析表明，V174A、R57Q 和 P155T 变体、一种新的移码插入、OATP1B114 和 OATP1B115 单倍型与西立伐他汀摄取的显著减少（P<0.001）相关（分别为参考值的 32%、18%、72%、3.4%、2.1%和 5.7%）。此外，氯吡格雷和其他七种药物被证明抑制 OATP1B1 介导的西立伐他汀摄取。
与遗传变异和药物相互作用相关的 OATP1B1 功能降低可能导致西立伐他汀引起的横纹肌溶解。尽管西立伐他汀已不再临床应用，但这些发现可能适用于相关的他汀类药物和其他 OATP1B1 的底物。
