Biotransformation and hepatotoxicity of halothane

Brown, B. R.; Sipes, I. G.

doi:10.1016/0006-2952(77)90256-8

Cited by 86 publications

(22 citation statements)

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“…However, it is unlikely to be directly related to the rare, late-onset, and severe form of ''halothane hepatitis'' in which the operation of immune mechanisms seems likely. [1][2][3][4][5][6] Similarly, there are no apparent clinical implications of the results reported in this experimental model of halothane-related liver injury.…”

Section: Effects Of Halothane On Passage Of Horseradish Per-discussionmentioning

confidence: 99%

“…In isolated perfused liver experi-mental models. [1][2][3][4][5][6] It is evident that metabolism of haloments, livers from halothane-exposed animals did not thane is usually required, but the manner in which this differ in hepatic oxygen uptake or in perfusion pressure leads to the onset of hepatocellular necrosis a few days at the end of experiments, but bile flow and biliary bile later is not known. The guinea pig model of halothanesalt concentrations were reduced.…”

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Impaired bile flow and disordered hepatic calcium homeostasis are early features of halothane-induced liver injury in guinea pigs

FROST¹

1996

Hepatology

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is quantitatively more important. (HEPATOLOGY 1996; To characterize the early events in liver injury pro-23:80-86.) duced by halothane, experiments were performed in genetically susceptible guinea pigs 19 hours after halothane exposure. Serum bile acid concentrations were Many studies have addressed the relationships befourfold increased in halothane-exposed animals com-tween halothane metabolism and liver injury in experipared with controls. In isolated perfused liver experi-mental models. [1][2][3][4][5][6] It is evident that metabolism of haloments, livers from halothane-exposed animals did not thane is usually required, but the manner in which this differ in hepatic oxygen uptake or in perfusion pressure leads to the onset of hepatocellular necrosis a few days at the end of experiments, but bile flow and biliary bile later is not known. The guinea pig model of halothanesalt concentrations were reduced. Hepatic calcium coninduced liver injury is of some interest to the human tent was increased in halothane-exposed guinea pigs counterpart because there is no requirement for induccompared with controls, and further experiments were performed to explore the reason for this. As determined tion of drug-metabolizing enzymes or for deliberate proby infusion of 45 Ca to steady-state perfusate concentra-duction of systemic hypoxia. 7-10 However, it is apparent tions, hepatic calcium clearance was increased in halo-from the temporal development of hepatic necrosis and thane-exposed guinea pigs compared with controls (0.37 the similar severity after single and multiple exposures { 0.06 vs. 0.28 { 0.02 mL/min, P õ .01). Decreased biliary to halothane 7,11 that immunologic mechanisms are unexcretion of calcium was also noted and was entirely likely to be operative in the guinea pig model, as they attributable to reduced bile flow. However, although de-appear to be in humans. Rather, a relationship to halocreased excretion contributed to hepatic accumulation thane metabolism with production of reactive metaboof calcium, it was quantitatively less important than enlites 7,10 and lipid peroxidation 12 or production of hepatic hanced hepatic uptake. As indicated by passage of a boischemia through halothane-induced reduction of helus of horseradish peroxidase from perfusate into bile, hepatic tight junction permeability was increased five-patic blood flow 13 have been proposed as mediating fold after halothane exposure. It is concluded that chole-liver injury. stasis, as exemplified by reduced bile flow, is an earlyAn advantage of the guinea pig model is that the feature of the liver injury produced by halothane in predisposition to hepatotoxicity is a genetically deterguinea pigs and is associated with increased tight junc-mined property that remains constant among individtion permeability. Although the decrease in bile flow ual animals. 8,14 Thus, susceptibility or resistance to contributes to an early increase in hepatic calcium con-halothane-induced liver injury can be characterized, tent, entry of calcium from the perfusi...

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Section: Effects Of Halothane On Passage Of Horseradish Per-discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Impaired bile flow and disordered hepatic calcium homeostasis are early features of halothane-induced liver injury in guinea pigs

FROST¹

1996

Hepatology

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“…Both minor and severe forms of liver damage have been reported in patients receiving methyl dopa. The former consists of asymptomatic, and often transient, rises of serum transaminases and according to various reports is found in two to 10 % of patients receiving the drug ( Brown &Sipes ,1977 andKshirsagar, 2008). The liver damage, which may take the form of acute hepatitis, chronic active hepatitis or cholestasis occurs more commonly in women and there is not the same close temporal relationship between the time of onset of overt clinical hepatic injury, which in 50 % of cases occurs after four weeks.…”

Section: Anti-hypertensive Drugsmentioning

confidence: 99%

Side Effects and Biochemical Changes in Rat Liver on Drug Treatment

2016

IJSR

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Antibiotics are the therapeutic agents most often associated with hepatotoxicity mainly due to the widespread prescription of these drugs. Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult, particularly because some cases occur long after the drug has been stopped. Among the penicillins, amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations. Flucloxacillin ranks as the second highest cause of DILI in many countries. The severity of antibiotic-induced DILI varies widely, with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestatic/mixed type. The pattern is strongly influenced by age. Recently telithromycin (a new generation macrolide) has been linked with DILI, with a typical pattern, which includes abrupt commencement of fever, abdominal pain, jaundice and, in some cases, ascites. Antibiotic-induced DILI appears to be idiosyncratic. Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity.

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“…MORRIS, R. (1976 (Inman & Mushin, 1978). Minor highly reactive metabolites of the drug are probably responsible for the liver damage and hepatotoxicity in animals occurs only after induction of the microsomal enzymes (Brown & Sipes, 1977). It is possible that halothane anaesthesia itself causes induction of drug metabolizing enzymes thus making hepatotoxicity more likely after a second administration within a few weeks.…”

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Microsomal enzyme induction after halothane anaesthesia [letter]

Nimmo¹,

Thompson²,

Prescott³

1981

Brit J Clinical Pharma

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LETTERS TO THE EDITORS 433terapia della tubercolosi, sui contegno degli indici biologici e degli effeti collaterali. G. Pneumonol., 12, 390-402. MORRIS, R. (1976 (Inman & Mushin, 1978). Minor highly reactive metabolites of the drug are probably responsible for the liver damage and hepatotoxicity in animals occurs only after induction of the microsomal enzymes (Brown & Sipes, 1977). It is possible that halothane anaesthesia itself causes induction of drug metabolizing enzymes thus making hepatotoxicity more likely after a second administration within a few weeks. Changes in hepatic drug metabolism during the 4 weeks following halothane anaesthesia do not seem to have been investigated in man. We report here the preliminary results of such a study in which the plasma antipyrine half-life was used as an index of drug metabolizing capacity.The plasma antipyrine half-life was measured on three occasions in five women (mean + s.d. age 35.8 + 6.6 years) and weight 56.3 + 5.6 kg) undergoing lower abdominal hysterectomy under general anaesthesia: (a) the day before surgery, (b) 1 week after, (c) 4 weeks after surgery. None of the patients was taking any medication before the study but one patient smoked 20 cigarettes per day.All received pethidine 50 mg and promazine 25 mg intramuscularly as premedication and anaesthesia was induced with thiopentone 350 mg. Pancuronium 6 mg was given and the lungs were ventilated with halothane 0.5 or 1% in oxygen 33% and nitrous oxide 66%. Surgery lasted 45-70 min (mean 56.3 + 11 min) and neuromuscular blockade was reversed by neostigmine 2.5 mg and atropine 1.2 mg. All received diamorphine S mg (7 or 8 doses at 6 hourly intervals) for post-operative pain but none was taking any medication at the times of the studies.

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Biotransformation and hepatotoxicity of halothane

Cited by 86 publications

References 44 publications

Impaired bile flow and disordered hepatic calcium homeostasis are early features of halothane-induced liver injury in guinea pigs

Impaired bile flow and disordered hepatic calcium homeostasis are early features of halothane-induced liver injury in guinea pigs

Side Effects and Biochemical Changes in Rat Liver on Drug Treatment

Microsomal enzyme induction after halothane anaesthesia [letter]

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