Isolation and characterization of metabolites of centpropazine in rat liver, intestine, and red blood cell homogenates

Atul, Bhattaram V.; Singh, Shio Kumar; Madhusudanan, K. P.; Paliwal, Jyoti; Gupta, R. C.

doi:10.1002/jps.10196

Cited by 4 publications

(3 citation statements)

References 10 publications

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“…(Owen and Natatsu, 1983;Awasthi and Singh, 1984;Mieyal, 1985;Helander and Tottmar, 1987;Ericsson et al, 1999). Atul et al (2002) reported that the same metabolite of centpropazine was formed in rat liver S9, intestine, and RBCs. It provided support that the RBCs may share many metabolic enzymes with liver and intestine, and can act as an extrahepatic system for drug clearance.…”

Section: Miao Et Almentioning

confidence: 99%

Identification of the in Vitro Metabolites of 3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; β-Lapachone) in Whole Blood

Miao¹,

Song²,

Savage³

et al. 2008

Drug Metab Dispos

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ABSTRACT:3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; ␤-lapachone) showed promising anticancer activity in phase I clinical trials as monotherapy and in combination with cytotoxic drugs. ARQ 501 is currently in multiple phase II clinical trials. In vitro incubation in fresh whole blood at 37°C revealed that ARQ 501 is stable in plasma but disappears rapidly in whole blood. Our data showed that extensive metabolism in red blood cells (RBCs) was mainly responsible for the rapid disappearance of ARQ 501 in whole blood. By comparison, covalent binding of ARQ 501 and/or its metabolites to whole blood components was a minor contributor to the disappearance of this compound. Sequestration of intact ARQ 501 in RBCs was not observed. Cross-species metabolite profiles from incubating [ 14 C]ARQ 501 in freshly drawn blood were characterized using a liquid chromatography-mass spectrometry-accurate radioactivity counter. The results show that ARQ 501 was metabolized more rapidly in mouse and rat blood than in dog, monkey, and human blood, with qualitatively similar metabolite profiles. Six metabolites were identified in human blood using ultra-high performance liquid chromatography/time-of-flight mass spectrometry, and the postulated structure of five metabolites was confirmed using synthetic standards. We conclude that the primary metabolic pathway of ARQ 501 in human blood involved oxidation of the two adjacent carbonyl groups to produce dicarboxylic and monocarboxylic metabolites, elimination of a carbonyl group to form a ring-contracted metabolite, and lactonization to produce two metabolites with a pyrone ring to form a ring-contracted metabolite. Metabolism by RBCs may play a role in clearance of ARQ 501 from the blood compartment in cancer patients.

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Section: Miao Et Almentioning

confidence: 99%

Identification of the in Vitro Metabolites of 3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; β-Lapachone) in Whole Blood

Miao¹,

Song²,

Savage³

et al. 2008

Drug Metab Dispos

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show abstract

“…Although applications of mass spectral analyses of targeted small molecules in erythrocytes using LC/ESI-MS [25], GC/MS [25,26] and targeted analysis of drugs and metabolites in biological fluids [27][28][29][30] has previously been described, much less is known of the metabolomic profile of erythrocytes.…”

Section: Introductionmentioning

confidence: 99%

A sample extraction and chromatographic strategy for increasing LC/MS detection coverage of the erythrocyte metabolome

Sana

Waddell

Fischer

2008

Journal of Chromatography B

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“…Some of the drugs studied by them include bulaquine (analog of primaquine), diastereomers of arteether, centbutindole, centpropazine, and some new chemical entities developed by CDRI, Lucknow. [182][183][184][185][186][187][188][189][190][191][192][193] S.K. Singh and colleagues from CDRI have carried out pharmacokinetics studies of many known and promising drug molecules in animal plasma using LC-ESI-MS/MS methods.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Mass Spectrometry in India

Vairamani

Prabhakar

2012

Eur J Mass Spectrom (Chichester)

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All rights reserved EUROPEAN JOURNAL OF MASS SPECTROMETRY This review highlights the research in mass spectrometry carried out all over India, with a focus on the last two decades. There has been a phenomenal increase in the use of mass spectrometers in India during the last decade following the introduction, at the beginning of the 21st century, of rugged electrospray ionization sources for the commercially available instruments, with applications such as pharmacokinetics and bio-equivalence drug studies, pesticide residue analysis and proteomics. There have been more papers published in these areas than could be fully covered in this article. This review covers mostly research in mass spectrometry carried out continuously in institutions where advanced facilities for mass spectrometry are functional. Researchers in India, with some notable exceptions, have always used and still use commercial mass spectrometers in their various areas of research, rather than develop their unique instruments. The review is divided into three parts: organic, elemental (or atomic) and biological mass spectrometry. Organic mass spectrometry Organic and bio-organic chemistry Research in organic mass spectrometry in the early years was mainly focused on the study of mass spectral fragmentation of different classes of new compounds,and was initiated in the 1960s by the late Das and his colleagues from the National Chemical Laboratory (NCL), Pune. The first double-focusing mass spectrometer (CEC-110 B) was installed at NCL for high-resolution mass measurements. The compounds studied by Das and his colleagues included aromatic amides, Benzophenanthridine derivatives, norses

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Isolation and characterization of metabolites of centpropazine in rat liver, intestine, and red blood cell homogenates

Cited by 4 publications

References 10 publications

Identification of the in Vitro Metabolites of 3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; β-Lapachone) in Whole Blood

Identification of the in Vitro Metabolites of 3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; β-Lapachone) in Whole Blood

A sample extraction and chromatographic strategy for increasing LC/MS detection coverage of the erythrocyte metabolome

Mass Spectrometry in India

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