Search for metabolites of ecteinascidin 743, a novel, marine-derived, anti-cancer agent, in man

Rw, Sparidans; Rosing, Hilde; Mj, Hillebrand; López-Lázaro, Luis; Jm, Jimeno; María, Ignacio; C, van Kesteren; Cvitkovic, Esteban; At, van Oosterom; Jh, Schellens; Beijnen, J. H.

doi:10.1097/00001813-200109000-00003

Cited by 25 publications

(27 citation statements)

References 16 publications

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“…Although of great interest, attempts to structurally identify the trabectedin metabolites have been unsuccessful (6,7). It is known, however, that trabectedin is metabolized to a plethora of metabolites, each likely to have a different toxicity profile and different affinities toward drug transporters.…”

Section: Discussionmentioning

confidence: 99%

“…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). Consequently, there is also only very limited evidence on whether the trabectedin metabolites are pharmacodynamically active or could in part be responsible for the trabectedin-mediated hepatotoxicity.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…25 It has been suggested that hepatic CYP3A activity upregulated by dexamethasone resulted in, or contributed to, the hepatoprotective action of dexamethasone by efficiently clearing ET-743 via nonhepatotoxic metabolites. 8 As hepatoprotection afforded by I3C may involve an analogous mechanism, its ability to induce CYP3A enzymes was investigated.…”

Section: Effect Of I3c On Levels Of Et-743 In Liver and Plasma And Onmentioning

confidence: 99%

Dietary agent indole‐3‐carbinol protects female rats against the hepatotoxicity of the antitumor drug ET‐743 (trabectidin) without compromising efficacy in a rat mammary carcinoma

Donald

Verschoyle

Greaves

et al. 2004

Intl Journal of Cancer

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ET-743, an experimental antitumor drug with promising activity in sarcoma, breast and ovarian carcinoma, is currently under phase 2 clinical evaluation. It is hepatotoxic in animals and patients. We tested the hypothesis that indole-3-carbinol (I3C), the hydrolysis product of glucosinolates occurring in cruciferous vegetables, may protect against ET-743-induced hepatotoxicity in the female Wistar rat, the animal species with the highest sensitivity toward the adverse hepatic effect of this drug. Hepatotoxicity was adjudged by measurement of plasma levels of bilirubin, alkaline phosphatase (ALP) and aspartate aminotransferase ( Key words: indole-3-carbinol; chemoprevention; ET-743; hepatotoxicityET-743 (ecteinascidin 743, trabectidin, Yondelis) is a tetrahydroisoquinoline alkaloid isolated from the marine tunicate Ecteinascidia turbinata. It possesses potent antineoplastic activity against a variety of human tumor xenografts grown in athymic mice, including melanoma and ovarian and breast carcinoma. [1][2][3] In clinical phase 1 studies of ET-743, promising responses were observed in patients with sarcoma, as well as breast and ovarian carcinoma, 4,5 and the drug is currently under intense investigation in a variety of phase 2 trials in cancer patients. However, myelotoxicity is dose-limiting. Furthermore, hepatotoxicity is frequently observed in the clinic, as reflected by reversible transaminitis and subclinical cholangitis, characterized by increases in alkaline phosphatase (ALP) and/or bilirubin. Treatment with ET-743 caused an increase in plasma levels of liver-specific enzymes and pathologic manifestations of cholangitis in most animal species in which it has been tested. 6,7 We recently showed that high-dose dexamethasone protects rats from ET-743-induced hepatotoxicity without compromising its antitumor activity. 8 Hepatoprotection was probably the consequence of a dramatic reduction by dexamethasone of hepatic levels of ET-743, which in turn was reasoned to be related to the ability of dexamethasone to increase the rate of metabolic detoxification of ET-743 via induction of the cytochrome P450 enzyme CYP3A in the liver. The potential use of high-dose dexamethasone as a hepatoprotectant in humans might be confounded by adverse effects, including diabetes mellitus, hypertension, arrhythmias, hypokalemia, psychosis, peptic ulceration and susceptibility to infection. 9,10 Indole-3-carbinol (I3C) is the aglycone of glucobrassicin, a microconstituent of cruciferous vegetables such as broccoli and Brussels sprouts. I3C, which is generated by glycoside-hydrolyzing enzymes when plant cells are disrupted by processing, cooking or mastication, possesses chemopreventive properties against chemically induced tumors in rodents at a variety of sites. [11][12][13][14] Clinical pilot studies of I3C have been conducted in patients with recurrent respiratory papillomatosis 15 and cervical intraepithelial neoplasia. 16 There has also been a dose-finding study to prepare for its evaluation as a breast cancer preventive agen...

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“…In rats, less than 0.5% of the dose administered was recovered in bile as trabectedin, suggesting an important role for metabolism in the elimination of trabectedin [13]. Urinary excretion of trabectedin in man is reported to be less than 1% of the dose administered, and biliary excretion of unchanged trabectedin is also very low [14][15][16], indicating that metabolism is the major route of elimination. However, the pathways involved in the metabolism of trabectedin are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Isolation of metabolites from biological matrices and further structural elucidation is very difficult because of their very low concentrations [15]. Metabolic and degradation products were identified after incubation with human serum, liver microsomes, and UDP-glucuronyl transferase [14], and in vitro studies with liver microsomes suggest that trabectedin is mainly metabolized by CYP3A4 and to a minor extent by CYPs 2C9, 2C19, 2D6 and 2E1 [13,17].…”

Section: Introductionmentioning

confidence: 99%

Disposition and toxicity of trabectedin (ET-743) in wild-type and mdr1 gene (P-gp) knock-out mice

et al. 2009

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Summary Trabectedin is a novel anticancer drug active against soft tissue sarcomas. Trabectedin is a substrate for P-glycoprotein (P-gp), which is encoded by mdr1a/1b in rodents. Plasma and tissue distribution, and excretion of [ 14 C]-trabectedin were evaluated in wild-type and mdr1a/1b (−/−) mice. In parallel, we investigated the toxicity profile of trabectedin by serial measurements of blood liver enzymes and general pathology. [14 C]-trabectedin was extensively distributed into tissues, and rapidly converted into a range of unknown metabolic products. The excretion of radioactivity was similar in both genotypes. The plasma clearance of unchanged trabectedin was not reduced when P-gp was absent, but organs under wild type circumstances protected by P-gp showed increased trabectedin concentrations in mdr1a/1b(−/−) mice. Although hepatic trabectedin concentrations were not increased when P-gp was absent, mdr1a/1b(−/−) mice experienced more severe liver toxicity. P-gp plays a role in the in vivo disposition and toxicology of trabectedin.

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Search for metabolites of ecteinascidin 743, a novel, marine-derived, anti-cancer agent, in man

Cited by 25 publications

References 16 publications

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

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

Dietary agent indole‐3‐carbinol protects female rats against the hepatotoxicity of the antitumor drug ET‐743 (trabectidin) without compromising efficacy in a rat mammary carcinoma

Disposition and toxicity of trabectedin (ET-743) in wild-type and mdr1 gene (P-gp) knock-out mice

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