Authors' Affiliations: Divisions of Molecular Biology and Clinical Chemistry, The Netherlands Cancer Institute, and Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, the Netherlands.
Clin Cancer Res. 2010 Jan 1;16(1):130-40. doi: 10.1158/1078-0432.CCR-09-1321. Epub 2009 Dec 22.
Despite the extensive use of etoposide for the treatment of different malignant neoplasms, its main pharmacokinetic determinants are not completely defined. We aimed to study the impact of P-glycoprotein (P-gp/ABCB1) and the multidrug resistance proteins ABCC2 (MRP2) and ABCC3 (MRP3) on the pharmacokinetics of etoposide.
Abcb1a/1b(-/-), Abcc2(-/-), Abcc3(-/-), Abcb1a/1b;Abcc2(-/-), and Abcc2;Abcc3(-/-) mice were used to investigate the separate and combined impact of P-gp, Abcc2, and Abcc3 on the in vivo behavior of etoposide.
P-gp restricted the oral (re)uptake of unchanged etoposide, and mediated its excretion across the gut wall. In contrast, hepatobiliary excretion was almost entirely dependent on Abcc2. Yet, complete loss of Abcc2 did not result in elevated liver or plasma concentrations of etoposide. Instead, Abcc2(-/-) mice displayed an increased hepatic formation of etoposide glucuronide, which was secreted via Abcc3 from the liver to the blood circulation and eliminated with the urine. Combination Abcc2;Abcc3(-/-) mice had highly increased accumulation of etoposide glucuronide in their livers, whereas both single knockouts did not, indicating that Abcc2 and Abcc3 provide alternative pathways for the hepatic elimination of etoposide glucuronide.
P-gp, ABCC2, and ABCC3 significantly affect the pharmacokinetics of etoposide and/or etoposide glucuronide. Variation in transporter expression or activity may explain the high variation in oral availability of etoposide (25-80%) among cancer patients. However, despite the fact that substantial variations in transporter activity can occur, we believe that cancer patients are often relatively protected from etoposide toxicity due to overlapping functions of these transporters in the elimination of etoposide.
尽管依托泊苷广泛用于治疗各种恶性肿瘤，但它的主要药代动力学决定因素尚未完全确定。我们旨在研究 P-糖蛋白（P-gp/ABCB1）和多药耐药蛋白 ABCC2（MRP2）和 ABCC3（MRP3）对依托泊苷药代动力学的影响。
使用 Abcb1a/1b(-/-)、Abcc2(-/-)、Abcc3(-/-)、Abcb1a/1b;Abcc2(-/-) 和 Abcc2;Abcc3(-/-) 小鼠来研究 P-gp、Abcc2 和 Abcc3 对依托泊苷体内行为的单独和联合影响。
P-gp 限制了未改变的依托泊苷的口服（再）摄取，并介导其穿过肠壁排泄。相比之下，肝胆排泄几乎完全依赖于 Abcc2。然而，完全缺失 Abcc2 并不会导致肝或血浆中依托泊苷浓度升高。相反，Abcc2(-/-) 小鼠显示出肝内依托泊苷葡萄糖醛酸苷形成增加，该物质通过 Abcc3 从肝脏分泌到血液循环中，并随尿液排出。组合 Abcc2;Abcc3(-/-) 小鼠肝脏中积累了高度增加的依托泊苷葡萄糖醛酸苷，而两种单敲除小鼠则没有，表明 Abcc2 和 Abcc3 为依托泊苷葡萄糖醛酸苷的肝消除提供了替代途径。
P-gp、ABCC2 和 ABCC3 显著影响依托泊苷及其葡萄糖醛酸苷的药代动力学。转运蛋白表达或活性的变化可能解释了癌症患者口服依托泊苷（25-80%）的高变异性。然而，尽管转运体活性可能会发生实质性变化，但我们认为，由于这些转运体在依托泊苷消除中的重叠功能，癌症患者通常相对受到依托泊苷毒性的保护。
