In vitro studies on the metabolism of trabectedin (YONDELIS®) in monkey and man, including human CYP reaction phenotyping

Vermeir, Marc; Hemeryck, Alex; Cuyckens, Filip; Francesch, Andrés; Bockx, Marc; Houdt, Jos Van; Steemans, Kathleen; Mannens, Geert; Avilés, Pablo; Coster, R. De

doi:10.1016/j.bcp.2009.02.020

Cited by 23 publications

(22 citation statements)

References 29 publications

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“…Vermier et al (2009) [358] recently extensively studied the metabolism of trabectedin in monkey and human liver microsomes. The authors found that the metabolite profiles of trabectedin at 5 M in Cynomolgus monkey and human liver microsomes were similar using 14 C-radiolabeled drug, although there was a higher abundance of the M4a/4b and M8b/8c metabolites in monkey fractions than in human fractions, suggesting a more active biotransformation of trabectedin via N-demethylation (to form M8b) and/or via demethylation with additional mono-oxidation (to form M4b), di-oxidation (to form M4a) or tri-oxidation (to form M8c) in monkeys than in humans [358].…”

Section: Ring Openingmentioning

confidence: 99%

“…M6a was the result of a combined demethylation and oxidation reaction at the A domain of the molecule, while M6b was likely the result from a demethylation and a mono-oxidation combined with a loss of two hydrogen atoms at the A domain of trabectedin. M8a was due to carboxylic acid formation at the A domain of the molecule; while M8b (ET-729) was formed by N-demethylation and M8c was likely the result of demethylation in combination with a triple oxidation, including an oxidation of the carbinolamine moiety to an amide, at the trabectedin A domain [358]. M9 was thought to be the result of an aliphatic ring opening at the methylene dioxybridge at the B subunit of trabectedin, whereas M16c was considered to be the result of an Odemethylation reaction at the C domain of trabectedin.…”

Section: Ring Openingmentioning

confidence: 99%

“…(36)) [358]. Another metabolite (M16c) resulted from Odemethylation at the trabectedin C subunit, and in addition, aliphatic ring opening of the methylene dioxybridge at the B domain yielded M9.…”

Section: Ring Openingmentioning

confidence: 99%

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Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

147

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Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

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Section: Ring Openingmentioning

confidence: 99%

Section: Ring Openingmentioning

confidence: 99%

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Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

147

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“…Trabectedin is extensively metabolized primarily through the CYP3A4 oxidative pathway, with lesser contributions from other CYP enzymes [47,48]. Fecal elimination is the primary route of excretion of trabectedin metabolites.…”

Section: Metabolism and Eliminationmentioning

confidence: 99%

Trabectedin

2009

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After completing this course, the reader will be able to:1. Enumerate the clinical indications for trabectedin therapy.2. Describe the mechanism of action and the pharmacokinetics of trabectedin.3. Analyze the toxicity profile and appraise the therapeutic effects associated with trabectedin.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME INTRODUCTIONTrabectedin (ET-743, Yondelis; Ortho Biotech Products, Horsham, PA) is a natural product that was originally isolated from the Caribbean sea squirt, Ecteinascidia turbinata but is now manufactured through an entirely synthetic route (Fig. 1) [1]. Trabectedin is a highly potent alkylator, and its cytotoxicity is thought to be mediated through a novel interaction with DNA repair pathways.

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“…Вследствие этого он пре-образуется во множество различных метаболитов. Ос-новные окислительные и деметилирующие изменения происходят в домене А. Домен С подвергается О-де-метилированию [9].…”

Section: Introductionunclassified