Binding of Radioactivity from 14C-labeled Halothane in Isolated Perfused Rat Livers

Dyke, Russell A. Van; Wood, Catherine L.

doi:10.1097/00000542-197304000-00005

Cited by 87 publications

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“…It is conceivable that the sites where we found non-extractable metabolites correspond to sites of biotransformation, i.e. where strongly reactive intermediates are formed, capable of immediate covalent binding to tissue constituents (Van Dyke & Wood 1973;Uehleke et al 1973). If so, metabolism of halothane seems to occur predominantly in the centrilobular zones of the liver, and in the respiratory epithelium (nasal mucosa, trachea and bronchial tree).…”

Section: Discussionmentioning

confidence: 94%

“…Whereas neurological disturbances by halothane are likely to be caused by the unchanged drug accumulating in the CNS, due to its lipid solu-bility, liver damage is most likely caused by reactive intermediates formed by metabolism in the hepatocytes (Van Dyke & Wood 1973;Van Dyke 1982; de Groot & Noll 1983). Reduced oxygen tension during anaesthesia has however been implicated as well (review Van Dyke 1982).…”

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confidence: 99%

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Accumulation in Murine Amniotic Fluid of Halothane and its Metabolites

Danielsson

Ghantous

Dencker

1984

Acta Pharmacologica et Toxicologica

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The distribution of radioactivity in pregnant mice was registered at 0, 1, 4, and 24 hrs after a 10 min. period of inhalation of 14C‐halothane. Autoradiographic methods were used to allow to distinguish between the distribution of volatile (non‐metabolized) halothane, water‐soluble metabolites, and firmly tissue‐bound metabolites. While volatile radioactivity was seen predominantly at short survival intervals, e.g. in body fat, blood, brain and liver, metabolites accumulated with time. Peak values occurred at 4 hrs in most organs (measured with liquid scintillation as well). The most remarkable findings were the high concentrations of radioactivity in amniotic fluid (and the ocular fluids of adults) with peak values at 4 hrs and rather high concentrations still prevailing at 24 hrs after inhalation. It is assumed that this activity represents only partly volaile halothane and mostly non‐volatile metabolites. High activity of metabolites was seen in the neuroepithelium of the embryo in early gestation. Firmly tissue‐bound metabolites, still remaining after washing the tissues with trichloroacetic acid and organic solvents, were found in the nasal mucosa, trachea and bronchial tree and in (presumably centrilobular) zones of the liver of adults after inhalation and 5‐day old mice after intraperitoneal injection, indicating the formation of reactive metabolites in these organs. Firmly tissue‐bound activity was not observed in the corresponding foetal organs.

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

Accumulation in Murine Amniotic Fluid of Halothane and its Metabolites

Danielsson

Ghantous

Dencker

1984

Acta Pharmacologica et Toxicologica

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“…The mechanism responsible for this has eluded any proven explanation but consistently has been linked to biotransformation, and covalent binding to vital subcellular macromolecules has been implicated (19). TFA and the concurrently formed metabolites, Br-and C1-are essentially nontoxic, and TFA has been shown not to bind (19,20). Cohen et al (21) have demonstrated the occurrence of organic metabolites other than TFA in human urine.…”

Section: Biotransformation and Toxicitymentioning

confidence: 99%

“…Van Dyke and his associates have elucidated the locations and determinants of irreversible binding of halothane metabolites in rat liver (19,20,(24)(25)(26)(27). Binding occurs in the microsomes (19), is inhibited by carbon monoxide (19,24) and SKF-525A (25), requires NADPH (24), is increased by pretreatment with phenobarbital (19) and polychlorobiphenyls (25), but not by methylcholanthrene (19,25), and is greatly accelerated by anaerobic conditions (24,26,27).…”

Section: Biotransformation and Toxicitymentioning

confidence: 99%

“…Binding occurs in the microsomes (19), is inhibited by carbon monoxide (19,24) and SKF-525A (25), requires NADPH (24), is increased by pretreatment with phenobarbital (19) and polychlorobiphenyls (25), but not by methylcholanthrene (19,25), and is greatly accelerated by anaerobic conditions (24,26,27). Under aerobic conditions in vivo, most binding is to microsomal proteins and phospholipids (24,27).…”

Section: Biotransformation and Toxicitymentioning

confidence: 99%

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Absorption, biotransformation, and storage of halothane

Holaday¹

1977

Environ Health Perspect

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Current knowledge of the quantitative aspects of biotransformation of halothane and the fate of its metabolites are reviewed. Absorbed quantities of the inhalation anesthetic average 12.7 and 18 g during 1 and 2 hr, respectively, of anesthesia. Reported fractions of halothane recovered as urinary metabolites range from 10 to 25%. An analysis of reports of bromide ion accumulation in plasma during and following anesthesia suggests that metabolism of halothane continues for 20-40 hr after exposure and that 22-24% of absorbed halothane is metabolized following 8 hr of anesthesia. Half-times for excretion of trifluoroacetic acid (TFA), a principal urinary metabolite of halothane, tend to confirm that biotransformation proceeds for 2 to 3 days following exposure. Other urinary metabolites which occur in small amounts include a dehydrofluorinated metabolite of halothane conjugated with L-cysteine and Ntrifluoroacetyl-n-ethanolamine, both of which are evidence of the occurrence of reactive intermediates during the metabolism of halothane. Support for free radical formation has come from in vivo and in vitro demonstrations of stimulation of lipoperoxidation of polyenoic fatty acids by halothane. Irreversible binding of halothane metabolites to microsomal proteins and phospholipids has been shown to depend on the microsomal P-450 cytochrome system. Irreversible binding is increased by microsomal enzyme induction and by anaerobic conditions. Hypoxia increases irreversible binding to phospholipids, augments the release of inorganic fluoride and is followed by centrilobular hepatic necrosis. It is concluded that one-fourth to one-half of halothane undergoes biotransformation in man. One fraction is excreted as trifluoroacetic acid, chloride and bromide. A second fraction is irreversibly bound to hepatic proteins and lipids. Under anaerobic conditions fluoride is released, binding to phospholipids is increased, and hepatic necrosis may occur.The purpose of this communication is to review current knowledge of the quantitative aspects of biotransformation of halothane and the fate of its metabolites. Absorbed DoseIn order to establish anesthesia as soon as possible, inhalation anesthesia is commonly initiated by using overpressure, i.e., an inspired concentration higher than the minimum alveolar concentration (MAC) (1) required to maintain anesthesia. Progressive reduction of the inspired concentration is employed to maintain a constant alveolar (and arterial blood) concentration. The whole body cumulative uptake depends on the solubility of the anesthetic in all the tissues, the volumes of the tissues and the rates of blood flow to the various tissues. Lowe (2) has shown, however, that the cumulative uptake Qn) required to achieve and maintain a constant

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Halothan [MAK Value Documentation in German language, 1979]

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Gesundheitsschädliche Arbeitsstoffe , 7. Lieferung, Ausgabe 1979 Der Artikel enthält folgende Kapitel: Allgemeiner Wirkungscharakter Erfahrungen beim Menschen Felderfahrungen Exposition, Metabolismus und Metabolitenexkretion Tierexperimentelle Befunde Akute Toxizität Chronische Toxizität Begründung des MAK‐Wertes

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Binding of Radioactivity from 14C-labeled Halothane in Isolated Perfused Rat Livers

Cited by 87 publications

References 0 publications

Accumulation in Murine Amniotic Fluid of Halothane and its Metabolites

Accumulation in Murine Amniotic Fluid of Halothane and its Metabolites

Absorption, biotransformation, and storage of halothane

Halothan [MAK Value Documentation in German language, 1979]

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