Overlapping functions of ABC transporters in topotecan disposition as determined in gene knockout mouse models.
Overlapping functions of ABC transporters in topotecan disposition as determined in gene knockout mouse models.
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DOI：
10.1158/1535-7163.mct-13-0100
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发表时间：
2013-07
影响因子：
5.7
通讯作者：
Gallo JM
中科院分区：
文献类型：
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作者：
Tiwari AK;Zhang R;Gallo JM
已确定ABC超家族的外排转运蛋白可通过与药物吸收、消除和分布有关的机制影响药物的药代动力学（PK）。为了表征多种转运蛋白在托泊替康PK中的作用，通过LC/MS/MS法测定了8种小鼠品系以1 mg/kg和4 mg/kg剂量IV给药后血浆、胆汁、尿液和粪便中的总（内酯+羧酸盐）和内酯形式; C57 BL/6（WT）、Abcb 1 −/−、Abcc 2 −/−、Abcc 4 −/−、Abcg 2 −/−、Abcc 2; Abcb 1 −/−、Abcc 2; Abcg 2 −/−、Abcc 4; Abcg 2 −/−。与WT小鼠相比，在两种剂量水平下，Abcc 2 −/−、Abcc 4 −/−、Abcb 1 −/−品系中托泊替康内酯的血浆曲线下面积（AUC）无显著差异，而Abcg 2 −/−、Abcc 2; Abcb 1 −/−（仅在高剂量下）、Abcc 4; Abcg 2 −/−和Abcc 2; Abcg 2 −/−小鼠中存在显著差异，范围为2.1倍至3.3倍。与这些变化一致，在基于Abcg 2 −/−的菌株中，托泊替康的粪便和胆汁排泄减少，而肾脏消除增加。同样，Abcc 2; Abcb 1 −/−菌株还具有托泊替康内酯的肾脏消除升高和粪便排泄减少，这在4 mg/kg剂量水平下更明显，表明Abcg 2可能饱和。发现Abcc 4转运蛋白不是拓扑替康PK的主要决定因素。可以得出结论，Abcg 2对拓扑替康消除具有最显著的作用，而Abcb 1和Abcc 2与Abcg 2具有重叠的功能。因此，研究这些转运蛋白中的多态性如何影响患者中的拓扑替康活性以及同时给予转运调节剂是否可以积极影响疗效而不增加毒性是相关的。
It is established that efflux transporters of the ABC superfamily can affect the pharmacokinetics (PKs) of drugs through mechanisms pertaining to drug absorption, elimination and distribution. To characterize the role of multiple transporters in topotecan's PKs, total (lactone+carboxylate) and lactone forms were measured by LC/MS/MS in plasma, bile, urine and feces following IV administration at doses of 1 mg/kg and 4 mg/kg to eight mouse strains; C57BL/6 (WT), Abcb1−/−, Abcc2−/−, Abcc4−/−, Abcg2−/−, Abcc2;Abcb1−/−, Abcc2;Abcg2−/−, Abcc4;Abcg2−/−. Compared with WT mice and at both dose levels, the plasma areas under the curve (AUC) for topotecan lactone were not significantly different in the Abcc2−/−, Abcc4−/−, Abcb1−/− strains, whereas significant differences were found in Abcg2−/−, Abcc2;Abcb1−/− (only at the high dose), Abcc4;Abcg2−/− and Abcc2;Abcg2−/− mice and ranged from 2.1-fold to 3.3-fold higher. Consistent with these changes, the fecal and biliary excretion of topotecan was reduced, while renal elimination was elevated in Abcg2−/− based strains. Similarly, the Abcc2;Abcb1−/− strain also had elevated renal elimination and reduced fecal excretion of topotecan lactone, this was more pronounced at the 4 mg/kg dose level, suggesting possible saturation of Abcg2. The Abcc4 transporter was found not to be a major determinant of topotecan PKs. It is concluded that Abcg2 has the most significant effect on topotecan elimination, whereas both Abcb1 and Abcc2 have overlapping functions with Abcg2. As such it is relevant to examine how polymorphisms in these transporters influence topotecan activity in patients and whether coadministration of transport modulators could positively affect efficacy without increasing toxicity.