The effects of inhibitors and substrates of different types of cytochrome P450 isozymes on serum dimethadione/trimethadione ratio in rats in vivo.
Trimethadione(TMO) is regarded as a model drug for estimating the hepatic drug oxidative capacity in vivo. However, the P450 isozymes that are responsible for TMO N-demethylation have not been identified clearly yet. This study was designed to determine these P450 isozymes that participate in the TMO N-demethylation in vivo by employing several typical P450 inhibitors and substrates. Male Sprague-Dawley(SD) rats were pretreated with P450 inhibitors or substrates before TMO(100mg/kg, p.o.) treatment. Serum dimethadione(DMO)/TMO ratios were employed for the assessment of metabolic capacity toward TMO. Pretreatment with imidazole and acetone significantly decreased the DMO/TMO ratios in a dose related manner. Weaker inhibitory effects were observed with SKF525A. However, pretreatment with alpha-naphthoflavone, quinine, debrisoquine, triacetyloleandomycin and lauric acid did not affect the ratios. These results suggest that various forms of P450 are involved in TMO metabolism to some extent and that CYP2E1 is attributed to major P450 isozyme for TMO N-demethylation in vivo.
Nishimura
Y
Y
Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan.
Kurata
N
N
Kobayashi
S
S
Uchida
E
E
Yasuhara
H
H
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D004114:Dimethadione / Q000097:blood*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D014293:Trimethadione / Q000097:blood*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D004114:Dimethadione; D014293:Trimethadione