Effect of H2-Receptor Antagonists on Acetaminophen-lnduced Hepatic Injury

Murase, Toshihiko; Hazama, Hiroshi; Okuno, Hiroyasu; Shiozaki, Yasuko; Sameshima, Yoshiko

doi:10.1254/jjp.41.467

Cited by 8 publications

(3 citation statements)

References 20 publications

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“…Mitchell et al (10) first showed that cimetidine, a H2-receptor antagonist that is known to inhibit the mixed-function oxi dase system in liver microsomes (9), pro tected against acetaminophen-induced liver injury. Murase et al (11) also reported that cimetidine markedly reduced acetaminophen induced liver injury, while ranitidine and famotidine, other H2-receptor antagonists that do not inhibit the mixed-function oxidase system (22,24), had little or no effect. Table 4.…”

Section: Discussionmentioning

confidence: 98%

“…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.…”

Section: Acceptedmentioning

confidence: 99%

“…Effects of ENX, NFLX and OFLX on acet aminophen-induced liver injury a) Pretreatment of animals: Male Fischer rats, each weighing 200 g, were fed a standard pellet diet and drinking water ad libitum. Ac cording to the method of Murase et al (11 ), the rats were injected intraperitoneally with a single dose of 3-methylcholanthrene (3-MC) (25 mg/kg) in olive oil to increase the sensi tivity of the rats to acetaminophen, and the rats in this induced state were used as the control. Rats were used for the experiments 72 hr after pretreatment with 3-MC after an overnight fast.…”

Section: Acceptedmentioning

confidence: 99%

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Comparison of Inhibitory Effects of New Quinolones on Drug Metabolizing Activity in the Liver

Nakanishi

Okuno

1990

Japanese Journal of Pharmacology

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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...

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Section: Discussionmentioning

confidence: 98%

Section: Acceptedmentioning

confidence: 99%

Section: Acceptedmentioning

confidence: 99%

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Comparison of Inhibitory Effects of New Quinolones on Drug Metabolizing Activity in the Liver

Nakanishi

Okuno

1990

Japanese Journal of Pharmacology

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Effect of nifedipine, verapamil, diltiazem and trifluoperazine on acetaminophen toxicity in mice

et al. 1995

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The hepatotoxicity of acetaminophen overdose depends on the metabolic activation to a toxic reactive metabolite by the hepatic mixed function oxidases. There is evidence that an increase in cytosolic Ca2+ is involved in acetaminophen hepatotoxicity. The effects of the Ca2+-antagonists nifedipine (NF), verapamil (V), diltiazem (DL) and of the calmodulin antagonist trifluoperazine (TFP) on the activity of some drug-metabolizing enzyme systems, lipid peroxidation and acute acetaminophen toxicity were studied in male albino mice. No changes in the drug-metabolizing enzyme activities studied and in the cytochrome P-450 and b5 contents were observed 1 h after oral administration of V (20 mg/kg). DL (70 mg/kg) and TFP (3 mg/kg). NF (50 mg/kg) increased cytochrome P-450 content, NADPH-cytochrome c reductase and ethylmorphine-N-demethylase activities. DL and TFP significantly decreased lipid peroxidation. NF, V, DL and TFP administered 1 h before acetaminophen (700 mg/kg orally) increased the mean survival time of animals. A large increase of serum aspartate aminotransferase(AST), and liver weight and depletion of liver reduced glutathione (GSH) occurred in animals receiving toxic acetaminophen dose. NF, V and DL prevented and TFP decreased the acetaminophen-induced hepatic damage measured both by plasma AST and by liver weight. NF, V, DL and TFP changed neither the hepatic GSH level nor the GSH depletion provoked by the toxic dose of acetaminophen. This suggests that V, DL and TFP do not influence the amount of the acetaminophen toxic metabolite formed in the liver. The possible mechanism of the protective effect of NF, V, DL and TFP on the acetaminophen-induced toxicity is discussed.

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