Abstract-The effects of six inducers and malotilate on 7-alkoxycoumarin 0 dealkylase activities in rat liver microsomes were examined. Phenobarbital (PB) (100 mg/kg) was administered intraperitoneally to rats for 6 days; 3-methylcholan threne (3-MC) (40 mg/kg), e9-naphthoflavone ((3-NF) (40 mg/kg), isosafrole (150 mg/kg) and polychlorinated biphenyls (PCB) (100 mg/kg) were administered intraperitoneally for 3 days; isoniazid (INH) (50 mg/kg) was administered intra peritoneally for 10 days; and malotilate (500 mg/kg) was administered orally for 3 days. The 0-dealkylase activities toward 7-methoxycoumarin (7-MC), 7 ethoxycoumarin (7-EC) and 7-propoxycoumarin (7-PC) were examined 24 hr after the final administration of the drugs. The ratios of 7-EC 0-deethylase and 7 PC 0-depropylase to 7-MC 0-demethylase activity in the control and six inducer treated groups were compared. The ratios in the groups treated with the six com pounds, each of which induces a different form(s) of cytochrome P-450 (P-450), were clearly different from each other. Therefore, the measurement of 7-alkoxy coumarin 0-dealkylase activities should be extremely useful for the routine deter mination of the molecular species of P-450. On the other hand, the ratio in the malotilate-treated group was different from that in any other inducer-treated group, so that there might be a possibility that malotilate induced a form(s) of P-450 that is different from any of the already known species.

Abstract-The effect of malotilate (diisopropyl 1,3-dithiol-2-ylidenemalonate) on drug metabolizing activity in rat liver microsomes was examined. Malotilte (500 mg/kg/day) was administered orally to rats for 3 days. The contents of cyto chrome P-450 (P-450) and cytochrome b5 (b5), the activity of NADPH-cytochrome c reductase, and the metabolization of aniline, aminopyrine, benzo(a)pyrene (B(a)P) and 7-ethoxycoumarin (7-EC) in the microsomal fraction were examined 24 hr after the final administration of malotilate. The content of b5 and the activity of NADPH-cytochrome c reductase were increased by the malotilate treatment, but the content of P-450 was not significantly affected. 7-EC 0-deethylation was markedly and aminopyrine N-demethylation was moderately enhanced; in contrast, aniline hydroxylation was significantly and B(a)P hydroxylation was slightly reduced. Such different effects of malotilate among the four substrate-me tabolizing activities may be due mainly to the increase in the content of b5, which participates in the transport of the second electron required for P-450 function to various extents. It is also possible that malotilate affects the population of P-450 subtypes, each having a different substrate specificity and a different affinity for b5.

Abstract-The effects of three new quinolones (enoxacin (ENX), norfloxacin (NFLX) and ofloxacin (OFLX)) on acetaminophen-induced liver injury in rats were examined and compared with their effects on the elimination half-life (T1/2) of theophylline (in vivo) and on the 7-ethoxycoumarin (7-EC) O-deethylase activity in liver microsomes (in vitro).ENX, NFLX and OFLX (75 or 300 mg/kg) were administered orally to rats 1 hr before, simultaneously with, and 1 hr after the acet aminophen injection (800 mg/kg). Biochemical liver function tests, drug me tabolizing activity in liver microsomes, the total glutathione content of the liver and histological changes were examined 5 hr after the acetaminophen injection. ENX markedly reduced acetaminophen-induced liver injury and NFLX slightly but sig nificantly did so, but no protective effect was observed with OFLX treatment. ENX markedly and NFLX slightly prolonged the T1/2 of theophylline, but OFLX did not affect it. In addition, ENX markedly and NFLX slightly inhibited the 7-EC Odeethylase activity in liver microsomes, but OFLX again had no effect. These findings indicated that ENX markedly inhibited the activity of cytochrome P-450 in liver microsomes and NFLX did so slightly, while OFLX had no such effect. Slight variations in the structures of these quinolones might explain the differences in their effects on cytochrome P-450 activity.In recent years, several new quinolones have been developed as effective antibacterial agents and widely used to treat a variety of infections. In 1984, Wijnands et al. (1) first reported that co-administration of enoxacin (ENX), one of the new quinolones, with theophylline raised the plasma theophylline concentration, and that eight of the ten pa tients who received theophylline in combina tion with ENX developed serious nausea and vomiting. Since then, many investigators have demonstrated that ENX raises the plasma theophylline concentration and prolongs its elimination half-life (T1 /2). In contrast, other new quinolones, such as norfloxacin (NFLX) and ofloxacin (OFLX), have no or only a slight effect on the pharmacokinetics of theophyl line (2-8). It appears that the increase in the plasma theophylline concentration is due to a reduced metabolic clearance of theophylline in the liver induced by ENX, while NFLX and OFLX seem to have little effect on drug metabolizing activity in the liver. However, little in vitro evidence has been reported that the new quinolones affect the activity of drug metabolizing enzymes in liver microsomes.Cimetidine, which is known to inhibit the drug metabolizing activity in liver microsomes (9), has been reported to prevent acetamino phen-induced liver injury (10, 11), but there have been no reports concerning the effects of the new quinolones on acetaminophen induced liver injury.In the present study, the protective effects of three new quinolones (ENX, NFLX and OFLX) on acetaminophen-induced acute liver injury in rats were investigated and com pared with each other. Moreover, the effects of these new quinolone...

No abstract