Metabolism of trabectedin (ET-743, Yondelis™) in patients with advanced cancer

Beumer, Jan H.; Rademaker-Lakhai, Jeany M.; Rosing, Hilde; Hillebrand, M. J. X.; Bosch, Tessa M.; López-Lázaro, Luis; Schellens, Jan H.M.; Beijnen, Jos H.

doi:10.1007/s00280-006-0342-2

Cited by 30 publications

(40 citation statements)

References 25 publications

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“…Extensive metabolism of trabectedin was demonstrated in a mass balance study conducted in patients with advanced cancer (Beumer et al, 2007b). Following i.v.…”

Section: Introductionmentioning

confidence: 99%

Modulation of trabectedin (ET-743) hepatobiliary disposition by multidrug resistance-associated proteins (Mrps) may prevent hepatotoxicity

Lee

Leslie

Zamek‐Gliszczynski

et al. 2008

Toxicology and Applied Pharmacology

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Trabectedin is a promising anticancer agent, but dose-limiting hepatotoxicity was observed during phase I/II clinical trials. Dexamethasone (DEX) has been shown to significantly reduce trabectedinmediated hepatotoxicity. The current study was designed to assess the capability of sandwichcultured primary rat hepatocytes (SCRH) to predict the hepato-protective effect of DEX against trabectedin-mediated cytotoxicity. The role of multidrug resistance-associated protein 2 (Mrp2; Abcc2) in trabectedin hepatic disposition also was examined. In SCRH from wild-type Wistar rats, cytotoxicity was observed after 24-hr continuous exposure to trabectedin. SCRH pretreated with additional DEX (1 µM) exhibited a 2-3-fold decrease in toxicity at 100 nM and 1000 nM trabectedin. Unexpectedly, toxicity in SCRH from Mrp2-deficient (TR − ) compared to wild-type Wistar rats was markedly reduced. Depletion of glutathione from SCRH using buthionine sulfoximine (BSO) mitigated trabectedin toxicity associated with 100 nM and 1000 nM trabectedin. Western blot analysis demonstrated increased levels of CYP3A1/2 and Mrp2 in SCRH pretreated with DEX; interestingly, Mrp4 expression was increased in SCRH after BSO exposure. Trabectedin biliary recovery in isolated perfused livers from TR − rats was decreased by ~75% compared to wild-type livers. In conclusion, SCRH represent a useful in vitro model to predict the hepatotoxicity of trabectedin observed in vivo. The protection by DEX against trabectedin-mediated cytotoxicity may be attributed, in part, to enhanced Mrp2 biliary excretion and increased metabolism by CYP3A1/2. Decreased trabectedin toxicity in SCRH from TR − rats, and in SCRH pretreated with BSO, may be due to increased basolateral excretion of trabectedin by Mrp3 and/or Mrp4.

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“…Extensive metabolism of trabectedin was demonstrated in a mass balance study conducted in patients with advanced cancer (Beumer et al, 2007b). Following i.v.…”

Section: Introductionmentioning

confidence: 99%

Modulation of trabectedin (ET-743) hepatobiliary disposition by multidrug resistance-associated proteins (Mrps) may prevent hepatotoxicity

Lee

Leslie

Zamek‐Gliszczynski

et al. 2008

Toxicology and Applied Pharmacology

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“…administration of ( 14 C)trabectedin to patients (6). No metabolites in plasma have been structurally identified so far and only a few metabolites from feces (6). The low dose and high volume of distribution, and long terminal half-life of trabectedin result in very low concentrations of trabectedin and its metabolites in plasma, urine, and feces, hampering the structural elucidation of the trabectedin metabolites (6,7).…”

mentioning

confidence: 99%

“…Indeed, a large number of (unknown) metabolites, without clearly predominating metabolites, could be observed in radiochromatograms after i.v. administration of ( 14 C)trabectedin to patients (6). No metabolites in plasma have been structurally identified so far and only a few metabolites from feces (6).…”

mentioning

confidence: 99%

ABCC2, ABCC3, and ABCB1, but not CYP3A, Protect against Trabectedin-Mediated Hepatotoxicity

Waterschoot

Eman²,

Wagenaar³

et al. 2009

Clinical Cancer Research

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Purpose: Trabectedin (Yondelis, ET-743) is a novel anticancer drug with potent activity against various tumors. However, dose-limiting hepatotoxicity was observed during clinical trials. Because recent reports have suggested that cytochrome P450 3A (CYP3A), as well as the drug transporters ABCB1, ABCC2, and ABCC3 might protect against trabectedin-mediated hepatotoxicity, we investigated the individual and combined roles of these detoxifying systems. Experimental Design: Madin-Darby canine kidney cells expressing ABCC2 and ABCC3 were used to study in vitro trabectedin transport. We investigated the hepatotoxicity of trabectedin, and the plasma and liver levels of this drug and its metabolites in mice deficient for CYP3A, Abcb1a/1b, Abcc2, and/or Abcc3 after i.v. trabectedin administration. Results: Trabectedin was transported by ABCC2 but only modestly by ABCC3. Contrary to our expectation, absence of CYP3A resulted in only a marginal increase in hepatotoxicity. Some hepatotoxicity was observed in Abcc2 -/-mice, but very little in Abcb1a/ 1b -/-and Abcc3 -/-mice. Strikingly, severe hepatotoxicity was found in Abcb1a/1b/ Abcc2 -/-and Abcc2/Abcc3 -/-mice. However, hepatotoxicity was drastically decreased in Cyp3a/Abcb1a/1b/Abcc2 -/-compared with Abcb1a/1b/Abcc2 -/-mice. This suggests that the formation of CYP3A-specific metabolites is an important prerequisite for trabectedin-mediated hepatotoxicity. Further studies revealed that there is increased accumulation of metabolites of trabectedin, but not of trabectedin itself, in the livers of mice that lack Abcc2 but are CYP3A proficient. Conclusions: Our data show that ABCB1, ABCC2, and ABCC3 have a profound and partially redundant function in protection from trabectedin-mediated hepatotoxicity, presumably by clearing the liver from hepatotoxic trabectedin metabolites that are primarily formed by CYP3A. (Clin Cancer Res 2009;15(24):7616-23) Trabectedin is an anticancer drug isolated from a marine tunicate that has recently been approved for the treatment of soft tissue carcinoma. In addition, several phases II and III clinical trials of trabectedin for treatment of other cancer types have been published or are still ongoing, including trials for breast (1), ovarian (2, 3), and prostate cancer (4). Although trabectedin has impressive antitumor activity, dose-limiting hepatotoxicity became apparent during several clinical trials (reviewed in ref. 5).Mass balance studies have revealed that trabectedin is extensively metabolized, and virtually all trabectedin is excreted in its metabolite form into bile. The chemical structure of trabectedin provides numerous sites for metabolic conversion. Indeed, a large number of (unknown) metabolites, without clearly predominating metabolites, could be observed in radiochromatograms after i.v. administration of ( 14 C)trabectedin to patients (6). No metabolites in plasma have been structurally identified so far and only a few metabolites from feces (6). The low dose and high volume of distribution, and long terminal half-l...

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“…Конечные продукты выводятся из организма в основном с калом, а часть с мочой в ви-де глюкуронидов. В неизмененном виде выводится не более 1 % трабектедина [10].…”

Section: Introductionunclassified

“…Точно так же индивидуальный полиморфизм фер-ментов CYP (3A4, 2C9, 2D6, 2C19, 2E1, GST-M1, P1, T1 и UGT1A1 2B15), выявленный в препаратах микро-сом из биоптатов больных, не отразился на общих по-казателях фармакодинамики и фармакокинетики тра-бектедина [10][11][12].…”

Section: Introductionunclassified