In vitro and in vivo metabolic studies of phospho-aspirin (MDC-22)

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.