Mass balance, excretion and metabolism of [14C] ASA404 in cancer patients in a phase I trial

McKeage, Mark J.; Fong, Peter; Hong, Xiuqin; Flarakos, Jimmy; Mangold, James B.; Du, Yancy; Tanaka, Chiaki; Schran, Horst

doi:10.1007/s00280-011-1809-3

Cited by 6 publications

(5 citation statements)

References 15 publications

(25 reference statements)

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“…In this study, the drug's mass balance was 86.9% in both urine and feces. The study also discovered two new metabolites of M7 and M10 in the pathway for the metabolism of this drug …”

Section: Introductionmentioning

confidence: 92%

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An overview on Vadimezan (DMXAA): The vascular disrupting agent

et al. 2018

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Vascular disrupting agents (VDAs), a group of cancer remedies, can cause a specific and irreversible destruction of established tumor vessels, and the complete halt of blood flow in the tumor. DMXAA (ASA404) or Vadimezan, a flavone-acetic acid-based drug, is the most promising VDAs that induces a rapid shutdown of blood flow in tumors but not in normal tissue. The exact mechanism of vascular disruption is unknown; however, proposed direct and indirect mechanisms of action for DMXAA comprises (i) inducing apoptosis in endothelial cells; (ii) hemorrhagic necrosis and ischemia in tumor; (iii) release of serotonin (5-HT); (vi) stimulation of innate immune system; (v) production of inflammatory cytokines, for example TNF, IL-6, GCSF, KC, IP-10, and MCP-1; (vi) activation of NFκB and p38 (MAPK); (vii) production of nitric oxide; and (viii) reducing tumor energetics and membrane turnover. Despite the remarkable results from preclinical and phase I/II, DMXAA has failed in phase III clinical trials. The reason for this surprising discrepancy, among others, was discovered to be STING receptor variations between mice and humans. In this review, the development, the mechanisms of DMXAA action, the clinical trials, the combination therapy, and the future of this drug will be discussed.

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“…In this study, the drug's mass balance was 86.9% in both urine and feces. The study also discovered two new metabolites of M7 and M10 in the pathway for the metabolism of this drug …”

Section: Introductionmentioning

confidence: 92%

“…The study also discovered two new metabolites of M7 and M10 in the pathway for the metabolism of this drug. [47]…”

Section: Phase I Clinical Trials Of Asa404: Single Agentmentioning

confidence: 99%

An overview on Vadimezan (DMXAA): The vascular disrupting agent

et al. 2018

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“…16). Both metabolites were detected in plasma and feces, and the dimer glucuronide conjugate was also detected in urine 72 .…”

Section: Metabolism and Eliminationmentioning

confidence: 97%

“…The resultant metabolites, namely DMXAA acyl glucuronide (DMXAA-G) (36, Fig.15) and 6hydroxymethyl-5-methylxanthenone-4 acetic acid (6-OH-MXAA) (37, Fig.15), have been successfully identified and quantified in different biological matrixes including animal and human plasma, urine, faeces and microsomes during PK, particularly metabolism studies 54,56,60,[63][64][65]67,68,72,198,200,[202][203][204] .…”

Section: Metabolism and Eliminationmentioning

confidence: 99%

“…However, it was eliminated mainly as metabolites. Actually, urinary and fecal excretion of unchanged DMXAA (2) accounted for only 10 and 20% or less of the dose, respectively 72 . Additionally, studies of DMXAA (2) metabolism by human intestinal Caco-2 cells revealed that DMXAA (2) was metabolized to a very small extent (up to 5%), suggesting that no considerable intestinal metabolism would take place when DMXAA (2) is orally administered 129 .…”

Section: Metabolism and Eliminationmentioning

confidence: 99%

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Drug-like Properties and ADME of Xanthone Derivatives: The Antechamber of Clinical Trials

Gomes¹,

Brandão²,

Fernandes³

et al. 2016

CMC

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Xanthone derivatives have been described as compounds with a privileged scaffold exhibiting diverse biological/pharmacological activities, what directed the interest to pursue the development of these derivatives into drug candidates. Nevertheless, to achieve this purpose it is crucial to study their pharmacokinetics and toxicity (PK/tox) properties as decision endpoints to continue or interrupt the development investment. This review aims to expose the most relevant analytical methods used in the physicochemical and PK/tox studies in order to detect, quantify, and identify different bioactive xanthones. Analyzing the main results from in vitro and in vivo systems towards ADME properties such as solubility, lipophilicity, pKa, chemical and metabolic stability, permeability, transporters modulation, and plasma protein binding, it is possible to uncover some threats governing the PK properties and to understand the bioavailability and drugability of xanthone derivatives. The last section of this review focuses on a case-study of the development of the drug candidate DMXAA, which has reached clinical trials, to provide the paths and the importance of PK/tox parameters of this scaffold. The data assembled in this review intends to guide for tackling issues in the design of potential lead compounds and drug candidates with a xanthone scaffold.

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