The effects of organic solvents on trimethadione n-demethylation in rats.
Many organic solvents are frequently used as support solvents to dissolve chemicals in the study concerning drug metabolism mediated by cytochrome P450. However, some organic solvents used as the support solvents affect the chemical's metabolism. It has been reported that some organic solvents are metabolized by CYP2E1 or inhibit its enzymatic reaction. In this study we investigated the effects of organic solvents, such as acetonitrile (AN), dimethylsulfoxide (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 were 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 mg/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 was 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-demethylase 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 activity was inhibited by DMSO, EtOH and PG with different potency in a concentration 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-mediated metabolism and AN and PEG will be useful solvents to dissolve chemicals in the metabolic study mainly mediated by CYP2E1.
Nishimura
Y
Y
Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan.
Kurata
N
N
Iwase
M
M
Li
H
H
Yasuhara
H
H
D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism; D004114:Dimethadione / Q000097:blood / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000008:administration & dosage / Q000494:pharmacology*; D014293:Trimethadione / Q000097:blood / Q000378:metabolism*
D000927:Anticonvulsants; D012997:Solvents; D004114:Dimethadione; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D014293:Trimethadione