Acetaminophen-induced Hepatic Necrosis

Jollow, David J.; Ss, Thorgeirsson; Potter, William Z.; Hashimoto, Masahisa; Mitchell, John R.

doi:10.1159/000136547

Cited by 515 publications

(120 citation statements)

References 18 publications

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“…Emerging case reports indicate that hepatotoxicity may also occur with chronic therapeutic use of paracetamol, even in the absence of risk factors such as chronic alcoholism and malnutrition [Bolesta and Haber, 2002]. Bioactivation of paracetamol to its toxic metabolite via cytochrome P450 (CYP) 2E1, and subsequent binding of the toxic metabolite to liver macromolecules is responsible for hepatocyte damage and death, as described in Table 3 [ Prescott, 1983;Jollow et al 1974;Mitchell et al 1973]. Liver biopsy reveals a centrilobular necrosis, with periportal sparing and little or no inflammatory reaction [Ward and AlexanderWilliams, 1999;Prescott, 1983].…”

Section: Pharmacokinetic Changesmentioning

confidence: 99%

Drug-induced liver injury in older adults

Mitchell

Hilmer

2010

Therapeutic Advances in Drug Safety

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Drug-induced liver injury (DILI) is an important cause of hospitalisation and of medication deregistration. In old age, susceptibility to DILI is affected by changes in physiology and increased interindividual variability, compounded by an increased prevalence of disease and the frailty syndrome. While dose-related or predictable DILI reactions are often detected in preclinical trials, the occurrence of rare hypersensitivity or idiosyncratic reactions cannot be reliably predicted from preclinical studies or even by clinical trials. The limited participation of older adults in clinical trials means that the susceptibility of this population to DILI is largely unknown. Vigilance during clinical trials and postmarketing surveillance must be universally practised. A systematic approach should be taken to determine not only which medicines are hepatotoxic and should be removed from the market, but also the hepatotoxicity risks from marketed drugs to consumers with different characteristics, many of whom are older people.

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Section: Pharmacokinetic Changesmentioning

confidence: 99%

Drug-induced liver injury in older adults

Mitchell

Hilmer

2010

Therapeutic Advances in Drug Safety

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“…However, in overdosage it can cause acute hepatic necrosis through the formation of a highly reactive intermediate metabolite by hepatic cytochrome P-450 dependent microsomal enzymes (Mitchell et al, 1973;Mitchell et al, 1974). In most laboratory animal species, the hepatotoxicity of paracetamol is increased by pretreatment with microsomal enzyme inducers such as phenobarbitone, 3-methyl-cholanthrene and ethanol and decreased by inhibitors such as piperonyl butoxide (Mitchell et al, 1973;Mitchell et al, 1974;Jollow et al, 1974;Strubelt, Obermeier & Siegers, 1978;Teschke, Stutz & Strohmeyer, 1979;Streeter & Timbrell, 1979).…”

Section: Introductionmentioning

confidence: 99%

Effects of microsomal enzyme induction on paracetamol metabolism in man.

Prescott¹,

Critchley²,

Balali-Mood³

et al. 1981

Brit J Clinical Pharma

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1 The metabolism of paracetamol after a single oral dose of 20 mg/kg was compared in fifteen patients with microsomal enzyme induction taking anticonvulsants or rifampicin and twelve healthy volunteers. 2 Induction was confirmed by measurement of the plasma antipyrine half‐ life (mean 6.4 h in the patients compared with 12.8 h in the volunteers). 3 The glucuronide conjugation of paracetamol was enhanced in the induced patients as shown by lower plasma paracetamol concentrations, a shorter paracetamol half‐life, higher paracetamol glucuronide concentrations and an increased ratio of the area under the plasma concentration time curves of the glucuronide to the unchanged drug. There were no significant differences in sulphate conjugation. 4 There was a corresponding change in the pattern of urinary metabolite excretion. The induced patients excreted significantly less unchanged drug and sulphate conjugate and more glucuronide conjugate than the healthy volunteers. 5 The urinary excretion of the mercapturic acid and cysteine conjugated of paracetamol was the same in both groups. 6 Conversion of paracetamol to its potentially hepatotoxic metabolite does not seem to be increased in patients induced with anticonvulsants or rifampicin. There would seem to be no contraindication to the use of these drugs in combination.

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“…Studies in experimental animals have shown that when higher doses are given, a reactive metabolite of the drug binds covalently with liver cell protein (5,7,8). Thorgeirsson et al (9) demonstrated that changes in bio chemical parameters were noted in both male mice and male hamsters after AAP admin istration.…”

Section: Abstract-studiesmentioning

confidence: 99%

Comparison of Effects of Acetaminophen on Liver Microsomal Drug Metabolism and Lipid Peroxidation in Rats and Mice

Satoh

Kitagawa

1978

Japanese Journal of Pharmacology

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Abstract-Studieswere conducted to determine the in vivo effect of acetaminophen (AAP) on the lipid peroxidation, drug metabolizing enzyme activity and microsomal electron transfer system of rat and mouse liver. AAP was found to inhibit ethyl morphine N-demethylase activity in the presence of NADPH and this inhibition of the enzyme was due to decrease in cytochrome P-450 content, but not due to change in lipid peroxidation in liver microsomes. Kinetical data showed that AAP administration had no effect on Km values of ethylmorphine N-demethylase, however, a decrease in the Vmax values was seen in rats and mice. There was no significant effect of AAP on both NADPH-cytochrome c reductase and the content of cytochrome b5 3 hours after this administration to rats and mice. On the other hand, AAP induced a signifi cant decrease in NADH-ferricyanide reductase in mice, but not in rats. The greatest decrease in cytochrome P-450 was observed among the components of the liver micro somal electron transfer system of rats and mice.Acetaminophen (AAP) is widely used as an analgesic, and its covalent binding to macromolecules has been reported when a large oral dose only of AAP was given (1, 2), and such may be attributed to production of hepatic necrosis in man (3). The drug is, however, remarkably safe in therapeutic doses (4).AAP is known to be metabolized by enzymes in liver microsomes and produces an active metabolite, N-hydroxy-acetaminophen (5, 6). Studies in experimental animals have shown that when higher doses are given, a reactive metabolite of the drug binds covalently with liver cell protein (5,7,8). Thorgeirsson et al. (9) demonstrated that changes in bio chemical parameters were noted in both male mice and male hamsters after AAP admin istration.Previous studies in this laboratory demonstrated that AAP has characteristics of type II substrate for microsomal mixed function oxygenase and inhibits ethylmorphine N demethylation in the noncompetitive type and aniline hydroxylation in the competitive one, respectively (10). It has been reported that mice were susceptible to the hepatotoxic effects of AAP, while rats were resistant to the AAP poisoning (2).The purpose of the present study was to investigate the comparison of the in vivo effects of AAP on drug metabolizing enzymes and lipid peroxidation in liver microsomes of rats and mice.

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Acetaminophen-induced Hepatic Necrosis

Cited by 515 publications

References 18 publications

Drug-induced liver injury in older adults

Drug-induced liver injury in older adults

Effects of microsomal enzyme induction on paracetamol metabolism in man.

Comparison of Effects of Acetaminophen on Liver Microsomal Drug Metabolism and Lipid Peroxidation in Rats and Mice

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