Background and Objectives: SM-1 is a new synthetic small molecular compound with anti-tumor activity. The metabolism of SM-1 is a key parameter that needs to be evaluated to provide further insight into drug safety and efficacy in the early phases of drug development.
Methods: In this study, the biotransformation process of SM-1, including the metabolic pathways and major metabolites, was investigated based on a liquid chromatography-mass spectrometry method. Upon incubation of SM-1 with human liver microsomes, five metabolites were identified, namely dihydrodiol formation (R1), hydroxylation (R2, R3, and R5), and debenzylation (R4) of SM-1, with R1 and R4 being the major metabolites. The enzyme kinetic parameters of SM-1 were determined by a liquid chromatography-tandem mass spectrometry method. The enzyme kinetics of SM-1 obeyed the Michaelis-Menten equation. The Vmax, Km, and CLint of SM-1 in HLMs were 14.5 nmol/mg protein/h, 6.32 μM, and 2.29 mL/mg protein/h, respectively.
Results: The chemical inhibition studies showed that CYP450 isoenzymes were responsible for SM-1 metabolism in HLMs, and CYP3A4 was the major CYP450 isoenzyme involved in the metabolism of SM-1; these findings were confirmed by using the human recombinant CYP3A4.
Conclusion: Through the identification of the biotransformation pathways and enzyme kinetics of SM-1, the metabolic enzymes for SM-1 in HLMs are characterized.
[http://dx.doi.org/10.1038/nchembio814] [PMID: 16936720]
[http://dx.doi.org/10.1021/jm900722z] [PMID: 19708658]
[http://dx.doi.org/10.1021/jm00163a024] [PMID: 2104934]
[http://dx.doi.org/10.2174/138920010794233503] [PMID: 20973757]
[http://dx.doi.org/10.1002/1099-0801(200010)14:6<351:AID-BMC28>3.0.CO;2-2] [PMID: 11002274]
[http://dx.doi.org/10.1124/dmd.31.7.815] [PMID: 12814957]
[http://dx.doi.org/10.1124/dmd.114.060996] [PMID: 25504504]
[http://dx.doi.org/10.3109/00498254.2014.945196] [PMID: 25070627]
[http://dx.doi.org/10.1124/dmd.112.045302] [PMID: 22645092]
[http://dx.doi.org/10.1177/0091270007312153] [PMID: 18378963]
[http://dx.doi.org/10.1016/j.jchromb.2008.10.006] [PMID: 18996064]
[http://dx.doi.org/10.2165/00003088-200645010-00002] [PMID: 16430309]
[http://dx.doi.org/10.1002/jps.22255] [PMID: 20564338]
[http://dx.doi.org/10.1016/j.clpt.2003.10.008] [PMID: 15001968]