Sex Differences in Halothane Metabolism and Hepatotoxicity in a Rat Model

Plummer, John L.; Hall, Pauline; Jenner, Mark A.; Cousins, Michael J.

doi:10.1213/00000539-198506000-00002

Cited by 9 publications

(7 citation statements)

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“…38 Thus, methionine-dependent pathways of PC synthesis may continue to operate, albeit at a lower level, in the presence of a dietary deficiency of methionine, allowing female rodents to retain their relative advantage over male rodents. Sex differences in metabolic pathways are well recognized in other rodent models of hepatic injury, 42 and in the hepatic metabolism of drugs in animals and humans. 43,44 Marked strain-related differences in steatosis were also identified in rats fed the MCD, with Wistar rats showing the greatest propensity to develop steatosis.…”

Section: Discussionmentioning

confidence: 99%

Rodent nutritional model of non‐alcoholic steatohepatitis: Species, strain and sex difference studies

Kirsch

Clarkson²,

Shephard

et al. 2003

J of Gastro and Hepatol

233

176

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Section: Discussionmentioning

confidence: 99%

Rodent nutritional model of non‐alcoholic steatohepatitis: Species, strain and sex difference studies

Kirsch

Clarkson²,

Shephard

et al. 2003

J of Gastro and Hepatol

233

176

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“…The hepatotoxicity of acetaminophen (16), carbon tetrachloride (17), isoniazid (Lauterburg, B. H. et al, Hepatology 1983;3:880, Abstract) and halothane (18) are reduced in rats pretreated with cimetidine, probably as a result of inhibited drug metabolism. These observations have led to the suggestion that cimetidine may be of use in the treatment of patients suffering from the toxic effects of acetaminophen overdose (19).…”

mentioning

confidence: 99%

Ranitidine–Acetaminophen Interaction: Effects on Acetaminophen–Induced Hepatotoxicity in Fischer 344 Rats

Leonard¹,

Morgan²,

Dent³

1985

Hepatology

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Cimetidine has been shown to protect against acetaminophen-mediated hepatotoxicity in both rats and mice. In contrast to cimetidine, ranitidine recently has been determined to potentiate the hepatotoxic action of acetaminophen in Fischer 344 rats. The present studies were designed to characterize this ranitidine-acetaminophen interaction. Acetaminophen administration (750 mg per kg, p.o.) to F344 rats produced maximal hepatic necrosis, 24 hr after treatment, as assessed by SGPT activity and histopathology. Ranitidine pretreatment 30 min prior to acetaminophen treatment increased the toxicity but did not alter its course. Ranitidine administration (50 mg per kg) enhanced acetaminophen hepatotoxicity throughout the toxic dose range of acetaminophen (600 to 1,000 mg per kg) and potentiation of acetaminophen hepatotoxicity by ranitidine was dose-dependent. Maximal increases were observed at 50 mg per kg ranitidine whereas, doses of ranitidine greater than 100 mg per kg inhibited acetaminophen toxicity. SGPT data were corroborated by histopathologic evaluation. Ranitidine was not hepatotoxic when administered alone (500 mg per kg), or following glutathione depletion, or after induction of hepatic mixed-function oxidase activity. The results obtained in these studies support the suggestion that, at high doses (greater than 100 mg per kg), ranitidine reduces acetaminophen hepatotoxicity by reducing metabolic activation, while at lower doses ranitidine potentiates acetaminophen hepatotoxicity. Inhibition by ranitidine of acetaminophen conjugation is proposed as a possible mechanism of this potentiation.

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“…In animal models, ranitidine slightly decreased the oxidative metabolism of halothane, while reductive pathways were no impaired (Plummer et al 1984). Furthermore, ranitidine did not provide protection against halothane-induced liver injury.…”

Section: Anaesthetic Agentsmentioning

confidence: 87%

Side Effects of Ranitidine

et al. 1991

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Ranitidine was first marketed in 1981; since then many patients have been treated such that much experience has been accumulated on the safety of this histamine H2-receptor antagonist in the treatment of gastroduodenal disease. A wide array of ranitidine-associated side effects has been described, but infrequently. As so much information is now available, the aim of this review is to assess the weight of evidence for a causal link between ranitidine and the reported side effects. Overall, ranitidine is well tolerated. The incidence of general side effects at less than 2% is very similar to placebo. Headaches, tiredness, dizziness and mild gastrointestinal disturbance (e.g. diarrhoea, constipation and nausea) are among the most frequent complaints, but have very seldom resulted in stopping treatment. Cardiovascular side effects are extremely rare and unpredictable with the usual doses of oral ranitidine (at most 1 in 1 million patients). They mostly comprise sinusal bradycardia and atrioventricular blockade, especially after rapid intravenous administration, receding after cessation of the drug. Clinical studies, however, have not shown a significant pharmacological effect of ranitidine on the cardiovascular system via H2-receptors, even though individual sensitivities cannot be ruled out in a few isolated reports. Ranitidine is unlikely to be directly hepatotoxic: a transient change in liver function tests has been noted in only 1 in 100 to 1 in 1000 patients. Several cases of mixed hepatitis have been reported, but very few were fully documented. The incidence of ranitidine-associated acute hepatitis has been estimated to be less than 1 in 100,000 patients. Neuropsychiatric complications may be less common and clinically quite similar to those reported with cimetidine, i.e. confusion, disorientation, hallucinations, delirium. These side effects have occurred especially in critically ill and multiple-therapy patients, or patients with chronic renal or hepatic failure, so that the direct causal link with ranitidine treatment was often difficult to ascertain. Even though an H2-receptor-mediated effect is an attractive hypothesis (since similar complications were noted with other H2-receptor antagonists), other mechanisms have been suggested to play a role, e.g. cholinergic or histaminic effects. The overall incidence of neuropsychiatric complications is probably markedly less than 1%. White cell injury (i.e. agranulocytosis) appears to be the most frequent haematological complication, even though case reports are very few and poorly documented.(ABSTRACT TRUNCATED AT 400 WORDS)

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Sex Differences in Halothane Metabolism and Hepatotoxicity in a Rat Model

Cited by 9 publications

References 0 publications

Rodent nutritional model of non‐alcoholic steatohepatitis: Species, strain and sex difference studies

Rodent nutritional model of non‐alcoholic steatohepatitis: Species, strain and sex difference studies

Ranitidine–Acetaminophen Interaction: Effects on Acetaminophen–Induced Hepatotoxicity in Fischer 344 Rats

Side Effects of Ranitidine

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