The effects of organic solvents on trimethadione N-demethylation in rats

Many organic solvents are frequently used as support solvents to dissolve c hemicals in the study concerning drug metabolism mediated by cytochrome P45 0. However, some organic solvents used as the support solvents affect the c hemical's metabolism. It has been reported that some organic solvents are m etabolized by CYP2E1 or inhibit its enzymatic reaction. In this study we in vestigated the effects of organic solvents, such as acetonitrile (AN), dime thylsulfoxide (DMSO), ethanol (EtOH), methanol (MeOH), polyethylene glycol (PEG) and propylene glycol (PG) on TMO (trimethadione) metabolism, which is mainly mediated by CYP2E1 in the rat. In the in vivo study, male SD rats w ere pretreated with an organic solvent intraperitoneally at a dosage of 0.5 , 1 or 2 mmol/kg 1 hour before TMO administration orally at the dose of 4 m g/kg. After 2 hours, serum concentrations of TMO and DMO were determined by gas chromatography/flame detection (CG/FTD) and the serum DMO/TMO ratio wa s employed for assessment of the metabolic capacity of TMO. In the in vitro study, hepatic microsomal fraction was used as an enzyme source of TMO N-d emethylase and enzyme activities were determined by the production of DMO. Pretreatment with DMSO and PG decreased the DMO/TMO ratio in a dose-related manner in vivo study. Furthermore, in vitro study TMO N-demethylase activi ty was inhibited by DMSO, EtOH and PG with different potency in a concentra tion related manner. However, no remarkable effects were observed by AN or PEG both in vivo and in vitro study. These results indicated that there are variations in the inhibitory effects of these organic solvents on CYP2E1-m ediated metabolism and AN and PEG will be useful solvents to dissolve chemi cals in the metabolic study mainly mediated by CYP2E1.