Department of Clinical Pharmacology, Ernst-Moritz-Arndt University Greifswald, Ferdinand-Sauerbruch-Strasse NK, Greifswald D-17475, Germany.
Radiology. 2012 Sep;264(3):741-50. doi: 10.1148/radiol.12112061. Epub 2012 Jul 6.
To determine if genetic polymorphisms of liver-specific human organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 influence cellular uptake of gadoxetic acid in vitro and if functionally relevant polymorphisms are confounders for liver enhancement by gadoxetic acid in healthy subjects.
This study received ethics approval, and all subjects provided written informed consent. Cellular uptake of gadoxetic acid by OATP1B1 and OATP1B3 and their frequent genetic variants was measured by using stable transfected embryonic kidney HEK293 cells. Liver signal intensity at gadoxetic acid-enhanced MR imaging and pharmacokinetics of gadoxetic acid were evaluated in 36 healthy carriers of SLCO1B1/1B3 wild-type alleles (n = 10), SLCO1B1*1b/1b (n = 8), SLCO1B115/15 (n = 7), SLCO1B15/15 (n = 1), SLCO1B11a/5 (n = 6), and SLCO1B34/*4 (n = 4) by using T1-weighted MR imaging and liquid chromatography tandem mass spectrometry.
Transport activity for gadoxetic acid was increased in cells transfected with SLCO1B1c.388A>G (12.8 pmol/[mg·min]6 3.53, P = .001) but decreased in cells with SLCO1B1c.388A>G/521T>C (3.11 pmol/[mg·min] ± 0.918, P = .004) compared with cells with nonvariant transporter (6.32 pmol/[mg·min] ± 2.73). Compared with activity of cells transfected with the nonvariant SLCO1B3 (7.43 pmol/[mg·min] ± 2.43), SLCO1B3c.699G>A was a gain-of-function variant (15.1 pmol/[mg·min] ± 5.52, P = .002), whereas SLCO1B3c.334T>G (0.364 pmol/[mg·min] ± 0.125, P = .0001) and SLCO1B3c.1564G>T (0.295 pmol/[mg·min] ± 0.247, P = .0001) were variants with lower function. Liver enhancement with gadoxetic acid was reduced in subjects with OATP1B1*1a/5 compared with wild-type subjects and those with OATP1B11b/1b (area under enhancement curve, 3-480 minutes in arbitrary units [au]; 20.7 au ± 6.85 vs 36.5 au ± 8.08 [P = .006] vs 34.6 au ± 8.92 [P = .026]). The OATP1B34 polymorphism was not of functional relevance. No pharmacokinetic characteristics of gadoxetic acid were influenced by genetic polymorphisms of OATP1B1 and OATP1B3.
Liver-specific OATP1B1 and OATP1B3 are uptake carriers for gadoxetic acid in subjects. Genetic polymorphisms of OATP1B1 are signal confounders in gadoxetic acid-enhanced liver MR imaging.
确定肝脏特异性有机阴离子转运多肽（OATP）1B1 和 OATP1B3 的基因多态性是否会影响体外细胞摄取钆塞酸，以及功能相关的多态性是否会影响健康受试者中由钆塞酸引起的肝增强。
本研究获得伦理批准，所有受试者均提供书面知情同意书。通过使用稳定转染的胚胎肾 HEK293 细胞测量 OATP1B1 和 OATP1B3 及其常见遗传变异体对钆塞酸的细胞摄取。在 36 名携带 SLCO1B1/1B3 野生型等位基因的健康携带者（n = 10）、SLCO1B1*1b/1b（n = 8）、SLCO1B115/15（n = 7）、SLCO1B15/15（n = 1）、SLCO1B11a/5（n = 6）和 SLCO1B34/*4（n = 4）中，通过 T1 加权磁共振成像和液相色谱串联质谱法评估钆塞酸增强磁共振成像的肝信号强度和钆塞酸的药代动力学。
与非变异转运体（6.32 pmol/[mg·min] ± 2.73）相比，转染 SLCO1B1c.388A>G（12.8 pmol/[mg·min]6 3.53，P =.001）的细胞中对钆塞酸的转运活性增加，而 SLCO1B1c.388A>G/521T>C（3.11 pmol/[mg·min] ± 0.918，P =.004）的细胞中转运活性降低。与非变异 SLCO1B3（7.43 pmol/[mg·min] ± 2.43）转染的细胞相比，SLCO1B3c.699G>A 是一种功能获得性变异体（15.1 pmol/[mg·min] ± 5.52，P =.002），而 SLCO1B3c.334T>G（0.364 pmol/[mg·min] ± 0.125，P =.0001）和 SLCO1B3c.1564G>T（0.295 pmol/[mg·min] ± 0.247，P =.0001）是功能较低的变异体。与野生型受试者和 SLCO1B1*1b/1b 受试者相比，OATP1B11a/5 受试者的钆塞酸肝增强降低（增强曲线下面积，3-480 分钟内任意单位[au]；20.7 au ± 6.85 vs 36.5 au ± 8.08[P =.006] vs 34.6 au ± 8.92[P =.026]）。OATP1B34 多态性无功能相关性。OATP1B1 和 OATP1B3 的遗传多态性不影响钆塞酸的药代动力学特征。
肝脏特异性 OATP1B1 和 OATP1B3 是受试者中钆塞酸的摄取载体。OATP1B1 的遗传多态性是钆塞酸增强肝磁共振成像的信号混杂因素。
