Metabolite profiling of the novel anti-cancer agent, plitidepsin, in urine and faeces in cancer patients after administration of 14C-plitidepsin

L van Andel; H Rosing; M M Tibben; L Lucas; R Lubomirov; P Avilés; A Francesch; S Fudio; A Gebretensae; M J X Hillebrand; J H M Schellens; J H Beijnen

doi:10.1007/s00280-018-3637-1

Metabolite profiling of the novel anti-cancer agent, plitidepsin, in urine and faeces in cancer patients after administration of 14C-plitidepsin

L van Andel, H Rosing, M M Tibben, L Lucas, R Lubomirov, P Avilés, A Francesch, S Fudio, A Gebretensae, M J X Hillebrand, J H M Schellens, J H Beijnen

Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
Pharma Mar, S.A., Colmenar Viejo, Madrid, Spain.

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

PURPOSE: Plitidepsin absorption, distribution, metabolism and excretion characteristics were investigated in a mass balance study, in which six patients received a 3-h intravenous infusion containing 7 mg 14C-plitidepsin with a maximum radioactivity of 100 µCi.

METHODS: Blood samples were drawn and excreta were collected until less than 1% of the administered radioactivity was excreted per matrix for two consecutive days. Samples were pooled within-patients and between-patients and samples were screened for metabolites. Afterwards, metabolites were identified and quantified. Analysis was done using Liquid Chromatography linked to an Ion Trap Mass Spectrometer and offline Liquid Scintillation Counting (LC-Ion Trap MS-LSC).

RESULTS: On average 4.5 and 62.4% of the administered dose was excreted via urine over the first 24 h and in faeces over 240 h, respectively. Most metabolites were found in faeces.

CONCLUSION: Plitidepsin is extensively metabolised and it undergoes dealkylation (demethylation), oxidation, carbonyl reduction, and (internal) hydrolysis. The chemical formula of several metabolites was confirmed using high resolution mass data.

Original language	English
Pages (from-to)	441-455
Number of pages	15
Journal	Cancer Chemotherapy and Pharmacology
Volume	82
Issue number	3
DOIs	https://doi.org/10.1007/s00280-018-3637-1
Publication status	Published - Sept 2018

Keywords

Aplidin
Plitidepsin
ADME
LC-MS/MS
Total radioactivity
Metabolite profiling

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00280-018-3637-1

van andelFinal published version, 1.01 MBLicence: Taverne

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van Andel, L., Rosing, H., Tibben, M. M., Lucas, L., Lubomirov, R., Avilés, P., Francesch, A., Fudio, S., Gebretensae, A., Hillebrand, M. J. X., Schellens, J. H. M., & Beijnen, J. H. (2018). Metabolite profiling of the novel anti-cancer agent, plitidepsin, in urine and faeces in cancer patients after administration of 14C-plitidepsin. Cancer Chemotherapy and Pharmacology, 82(3), 441-455. https://doi.org/10.1007/s00280-018-3637-1

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title = "Metabolite profiling of the novel anti-cancer agent, plitidepsin, in urine and faeces in cancer patients after administration of 14C-plitidepsin",

abstract = "PURPOSE: Plitidepsin absorption, distribution, metabolism and excretion characteristics were investigated in a mass balance study, in which six patients received a 3-h intravenous infusion containing 7 mg 14C-plitidepsin with a maximum radioactivity of 100 µCi.METHODS: Blood samples were drawn and excreta were collected until less than 1% of the administered radioactivity was excreted per matrix for two consecutive days. Samples were pooled within-patients and between-patients and samples were screened for metabolites. Afterwards, metabolites were identified and quantified. Analysis was done using Liquid Chromatography linked to an Ion Trap Mass Spectrometer and offline Liquid Scintillation Counting (LC-Ion Trap MS-LSC).RESULTS: On average 4.5 and 62.4% of the administered dose was excreted via urine over the first 24 h and in faeces over 240 h, respectively. Most metabolites were found in faeces.CONCLUSION: Plitidepsin is extensively metabolised and it undergoes dealkylation (demethylation), oxidation, carbonyl reduction, and (internal) hydrolysis. The chemical formula of several metabolites was confirmed using high resolution mass data.",

keywords = "Aplidin, Plitidepsin, ADME, LC-MS/MS, Total radioactivity, Metabolite profiling",

author = "{van Andel}, L and H Rosing and Tibben, {M M} and L Lucas and R Lubomirov and P Avil{\'e}s and A Francesch and S Fudio and A Gebretensae and Hillebrand, {M J X} and Schellens, {J H M} and Beijnen, {J H}",

year = "2018",

month = sep,

doi = "10.1007/s00280-018-3637-1",

language = "English",

volume = "82",

pages = "441--455",

journal = "Cancer Chemotherapy and Pharmacology",

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number = "3",

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van Andel, L, Rosing, H, Tibben, MM, Lucas, L, Lubomirov, R, Avilés, P, Francesch, A, Fudio, S, Gebretensae, A, Hillebrand, MJX, Schellens, JHM & Beijnen, JH 2018, 'Metabolite profiling of the novel anti-cancer agent, plitidepsin, in urine and faeces in cancer patients after administration of 14C-plitidepsin', Cancer Chemotherapy and Pharmacology, vol. 82, no. 3, pp. 441-455. https://doi.org/10.1007/s00280-018-3637-1

TY - JOUR

T1 - Metabolite profiling of the novel anti-cancer agent, plitidepsin, in urine and faeces in cancer patients after administration of 14C-plitidepsin

AU - van Andel, L

AU - Rosing, H

AU - Tibben, M M

AU - Lucas, L

AU - Lubomirov, R

AU - Avilés, P

AU - Francesch, A

AU - Fudio, S

AU - Gebretensae, A

AU - Hillebrand, M J X

AU - Schellens, J H M

AU - Beijnen, J H

PY - 2018/9

Y1 - 2018/9

N2 - PURPOSE: Plitidepsin absorption, distribution, metabolism and excretion characteristics were investigated in a mass balance study, in which six patients received a 3-h intravenous infusion containing 7 mg 14C-plitidepsin with a maximum radioactivity of 100 µCi.METHODS: Blood samples were drawn and excreta were collected until less than 1% of the administered radioactivity was excreted per matrix for two consecutive days. Samples were pooled within-patients and between-patients and samples were screened for metabolites. Afterwards, metabolites were identified and quantified. Analysis was done using Liquid Chromatography linked to an Ion Trap Mass Spectrometer and offline Liquid Scintillation Counting (LC-Ion Trap MS-LSC).RESULTS: On average 4.5 and 62.4% of the administered dose was excreted via urine over the first 24 h and in faeces over 240 h, respectively. Most metabolites were found in faeces.CONCLUSION: Plitidepsin is extensively metabolised and it undergoes dealkylation (demethylation), oxidation, carbonyl reduction, and (internal) hydrolysis. The chemical formula of several metabolites was confirmed using high resolution mass data.

AB - PURPOSE: Plitidepsin absorption, distribution, metabolism and excretion characteristics were investigated in a mass balance study, in which six patients received a 3-h intravenous infusion containing 7 mg 14C-plitidepsin with a maximum radioactivity of 100 µCi.METHODS: Blood samples were drawn and excreta were collected until less than 1% of the administered radioactivity was excreted per matrix for two consecutive days. Samples were pooled within-patients and between-patients and samples were screened for metabolites. Afterwards, metabolites were identified and quantified. Analysis was done using Liquid Chromatography linked to an Ion Trap Mass Spectrometer and offline Liquid Scintillation Counting (LC-Ion Trap MS-LSC).RESULTS: On average 4.5 and 62.4% of the administered dose was excreted via urine over the first 24 h and in faeces over 240 h, respectively. Most metabolites were found in faeces.CONCLUSION: Plitidepsin is extensively metabolised and it undergoes dealkylation (demethylation), oxidation, carbonyl reduction, and (internal) hydrolysis. The chemical formula of several metabolites was confirmed using high resolution mass data.

KW - Aplidin

KW - Plitidepsin

KW - ADME

KW - LC-MS/MS

KW - Total radioactivity

KW - Metabolite profiling

U2 - 10.1007/s00280-018-3637-1

DO - 10.1007/s00280-018-3637-1

M3 - Article

C2 - 29974200

SN - 0344-5704

VL - 82

SP - 441

EP - 455

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

IS - 3

ER -

Metabolite profiling of the novel anti-cancer agent, plitidepsin, in urine and faeces in cancer patients after administration of 14C-plitidepsin

Abstract

Keywords

UN SDGs

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