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In Vitro and In Vivo Metabolic Studies of Phospho-aspirin (MDC-22)

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Abstract

Purpose

To investigate the metabolism of phospho-aspirin (PA, MDC-22), a novel anti-cancer and anti-inflammatory agent.

Methods

The metabolism of PA was studied in the liver and intestinal microsomes from mouse, rat and human.

Results

PA is rapidly deacetylated to phospho-salicylic acid (PSA), which undergoes regioselective oxidation to generate 3-OH-PSA and 5-OH-PSA. PSA also can be hydrolyzed to give salicylic acid (SA), which can be further glucuronidated. PA is far more stable in human liver or intestinal microsomes compared to those from mouse or rat due to its slowest deacetylation in human microsomes. Of the five major human cytochrome P450 (CYP) isoforms, CYP2C19 and 2D6 are the most active towards PSA. In contrast to PSA, conventional SA is not appreciably oxidized by the CYPs and liver microsomes, indicating that PSA is a preferred substrate of CYPs. Similarly, PA, in contrast to PSA, cannot be directly oxidized by CYPs and liver microsomes, indicating that the acetyl group of PA abrogates its oxidation by CYPs.

Conclusions

Our findings establish the metabolism of PA, reveal significant inter-species differences in its metabolic transformations, and provide an insight into the role of CYPs in these processes.

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Abbreviations

ASA:

acetylsalicylic acid (aspirin)

CES:

carboxylesterases

CYP:

cytochrome P450

DFP:

diisopropyl fluorophosphate

HLM:

human liver microsomes

MLM:

mouse liver microsomes

RLM:

rat liver microsomes

PA:

phospho-aspirin

PSA:

phospho-salicylic acid

SA:

salicylic acid

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Acknowledgments and Disclosures

This work was supported by the Department of Defense grant W81XWH1010873 and National Institute of Health grant 5R01CA139454-03. We also thank R. Rieger and T. Koller, Stony Brook University, for their expert LC-MS/MS analysis of our samples and the shared instrumentation grant, NIH/NCRR 1S10 RR023680-1.

The authors have nothing to disclose except for BR, who has an equity position in Medicon Pharmaceuticals, Inc., and PPC who is affiliated with the same.

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Authors and Affiliations

  1. Stony Brook University, Division of Cancer Prevention, HSC, T17-080, Stony Brook, New York, 11794-8175, USA

    Gang **e, Chi C. Wong, Ka-Wing Cheng, Liqun Huang & Basil Rigas

  2. Medicon Pharmaceuticals, Inc., Stony Brook, New York, 11790, USA

    Panayiotis P. Constantinides

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  1. Gang **e
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  2. Chi C. Wong
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  3. Ka-Wing Cheng
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  6. Basil Rigas
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Correspondence to Basil Rigas.

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**e, G., Wong, C.C., Cheng, KW. et al. In Vitro and In Vivo Metabolic Studies of Phospho-aspirin (MDC-22). Pharm Res 29, 3292–3301 (2012). https://doi.org/10.1007/s11095-012-0821-6

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  • DOI: https://doi.org/10.1007/s11095-012-0821-6

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