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G B Corcoran

Publications and source records attributed to G B Corcoran.

49 records · Page 3Linked to original sources
PubMed1985

Effects of N-acetylcysteine on the disposition and metabolism of acetaminophen in mice.

N-acetylcysteine is the drug of choice for the treatment of acetaminophen poisoning, yet the mechanism of protection in vivo is unknown. Prevention of liver injury could result from decreased production of the toxic intermediate(s), from increased capacity to detoxify the toxic intermediate(s) or from increased ability of the tissue to withstand or even repair the molecular damage caused by the toxic species. Treatment of mice with N-acetylcysteine (1200 mg/kg p.o.) was found to prevent the hepatic damage caused by 1000 mg/kg p.o. of acetaminophen. Possible mechanisms for this hepatoprotective effect were examined by measurement at different time points of acetaminophen and its metabolites in plasma, urine, bile and whole-body homogenates and by evaluation of the changes in these parameters caused by treatment with N-acetylcysteine. A high-pressure liquid chromatographic method was developed to measure the majority urinary metabolites of acetaminophen and was validated by desorption chemical ionization mass spectral analysis of individual metabolites. Minimal differences in the concentration of unchanged acetaminophen and metabolites in whole-body homogenates at 4, 6 and 24 hr postdose were noted for N-acetylcysteine-treated vs. vehicle-treated mice. These results are incompatible with a decreased formation of the toxic species secondary to delayed acetaminophen absorption from the gastrointestinal tract or with an increased clearance of acetaminophen via nontoxic pathways such as sulfation as plausible mechanisms for the observed hepatoprotection.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1985

Effects of N-acetylcysteine on acetaminophen covalent binding and hepatic necrosis in mice.

Experiments were designed to test whether the protective effect of N-acetylcysteine against acetaminophen hepatotoxicity precedes arylation of tissue or whether protection occurs after arylation of tissue. Investigation of potential postarylation actions showed that N-acetylcysteine was unable to attenuate the liver necrosis caused by acetaminophen or several other hepatotoxins that act through chemically reactive metabolites. Furthermore, varying the time and route of N-acetylcysteine treatment indicated that the late protection against acetaminophen mortality probably was a consequence of pharmacokinetic factors rather than postarylation intervention in the process of cell death. The antidote was found to inhibit covalent binding of acetaminophen by about 70% when N-acetylcysteine protected against liver necrosis. Treatment regimens that had no effect upon covalent binding also had no effect on acetaminophen hepatotoxicity. Previous failures to detect this relationship apparently occurred because of a failure to consider biological events important in the pathophysiology of acetaminophen-induced necrosis, particularly the marked intrahepatic hemorrhage and vascular congestion with liver engorgement by protein and fluid. These results support the hypothesis that sulfhydryl nucleophiles such as N-acetylcysteine act primarily through prearylation mechanisms to decrease the amount of reactive metabolite available for initiation of hepatic injury.

Acetaminophen↗
PubMed1983

Mechanism of action of N-acetylcysteine in the protection against the hepatotoxicity of acetaminophen in rats in vivo.

N-Acetylcysteine is the drug of choice for the treatment of an acetaminophen overdose. It is thought to provide cysteine for glutathione synthesis and possibly to form an adduct directly with the toxic metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine. However, these hypothese have not been tested in vivo, and other mechanisms of action such as reduction of the quinoneimine might be responsible for the clinical efficacy of N-acetylcysteine. After the administration to rats of acetaminophen (1 g/kg) intraduodenally (i.d.) and of [(35)S]-N-acetylcysteine (1.2 g/kg i.d.), the specific activity of the N-acetylcysteine adduct of acetaminophen (mercapturic acid) isolated from urine and assayed by high pressure liquid chromatography averaged 76+/-6% of the specific activity of the glutathione-acetaminophen adduct excreted in bile, indicating that virtually all N-acetylcysteine-acetaminophen originated from the metabolism of the glutathione-acetaminophen adduct rather than from a direct reaction with the toxic metabolite. N-Acetylcysteine promptly reversed the acetaminophen-induced depletion of glutathione by increasing glutathione synthesis from 0.54 to 2.69 mumol/g per h. Exogenous N-acetylcysteine did not increase the formation of the N-acetylcysteine and glutathione adducts of acetaminophen in fed rats. However, when rats were fasted before the administration of acetaminophen, thereby increasing the stress on the glutathione pool, exogenous N-acetylcysteine significantly increased the formation of the acetaminophen-glutathione adduct from 57 to 105 nmol/min per 100 g. Although the excretion of acetaminophen sulfate increased from 85+/-15 to 211+/-17 mumol/100 g per 24 h after N-acetylcysteine, kinetic simulations showed that increased sulfation does not significantly decrease formation of the toxic metabolite. Reduction of the benzoquinoneimine by N-acetylcysteine should result in the formation of N-acetylcysteine disulfides and glutathione disulfide via thiol-disulfide exchange. Acetaminophen alone depleted intracellular glutathione, and led to a progressive decrease in the biliary excretion of glutathione and glutathione disulfide. N-Acetylcysteine alone did not affect the biliary excretion of glutathione disulfide. However, when administered after acetaminophen. N-acetylcysteine produced a marked increase in the biliary excretion of glutathione disulfide from 1.2+/-0.3 nmol/min per 100 g in control animals to 5.7+/-0.8 nmol/min per 100 g. Animals treated with acetaminophen and N-acetylcysteine excreted 2.7+/-0.8 nmol/min per 100 g of N-acetylcysteine disulfides (measured by high performance liquid chromatography) compared to 0.4+/-0.1 nmol/min per 100 g in rats treated with N-acetylcysteine alone. In conclusion, exogenous N-acetylcysteine does not form significant amounts of conjugate with the reactive metabolite of acetaminophen in the rat in vivo but increases glutathione synthesis, thus providing more substrate for the detoxification of the reactive metabolite in the early phase of an acetaminophen intoxication when the critical reaction with vital macromolecules occurs.

Acetaminophen↗
PubMed1976

Isoniazid and iproniazid: activation of metabolites to toxic intermediates in man and rat.

Acetylhydrazine, a metabolite of isoniazid, a widely used antituberculosis drug, and isopropylhydrazine, a metabolite of iproniazid, an antidepressant removed from clinical use because of high incidence of liver injury, were oxidized by cytochrome P-450 enzymes in human and rat liver microsomes to highly reactive acylating and alkylating agents. Covalent binding of these metabolites to liver macromolecules paralleled hepatic cellular necrosis. The metabolites formed from these and probably other monosubstituted hydrazines are reactive electrophiles.

Animals↗
PubMedDate not supplied

Obesity as a risk factor in drug-induced organ injury. V. Toxicokinetics of gentamicin in the obese overfed rat.

Obese human patients and obese overfed rats treated chronically with gentamicin suffer greater renal injury than nonobese patients and control animals. To understand the mechanism of this heightened susceptibility to the nephrotoxic effects of gentamicin, this study examines the plasma-time course and renal uptake of gentamicin in control and obese overfed rats following a single bolus dose. Gentamicin was administered ip to control rats at 30 mg/kg total body mass and to obese rats at 30 mg/kg ideal body mass plus 40% of excess body mass. Following gentamicin dosing, only 1 of 11 concentration-time points taken over 6/hr postdosing was different between control and obese groups. In addition, the area under the plasma concentration curve extrapolated to infinite time was not different between obese and control rats (mean +/- SD of 4.47 +/- 0.85 vs. 4.13 +/- 0.35 mg.min.ml-1, p greater than 0.5). The gentamicin plasma concentrations after 6 hr were less than 1 microgram/ml and not different between the groups; however, the concentration of gentamicin in the kidneys was 33% greater in obese than control rats at this time (324 +/- 66.9 vs. 244 +/- 34.7 micrograms/g, p less than 0.05). The fraction of dose and the total amount of drug that accumulated in the kidneys were also greater in the obese rats (42 and 72% increases). Considered with the results of previous studies, it appears that obese overfed rats sustain more severe nephrotoxicity following comparable plasma gentamicin exposure because of increased renal uptake and/or retention of drug.

Absorption↗
PubMedDate not supplied

An overfed rat model that reproduces acetaminophen disposition in obese humans.

This disposition of acetaminophen was examined in an overfed rat model of human obesity following iv administration of a subtoxic 303 +/- 5 mg/kg dose based upon ideal body weight. Weanling Sprague-Dawley rats were maintained on a nutritionally complete semisynthetic diet containing 60% vegetable shortening and were compared to animals given a standard laboratory diet over the same 22-week period. At the time of study obese rats outweighed controls by 42% (637 +/- 32 g vs. 450 +/- 7 g, respectively). The absolute clearance of acetaminophen from plasma increased by 27% in obese rats. Higher partial formation clearance to acetaminophen glucuronide and sulfate conjugates accounted for most of this increase. Clearance by sulfhydryl conjugation was also substantially increased (56%), indicating that metabolism via toxic oxidation also occurred at a greater rate in obese animals. Absolute renal clearance of the glucuronide and sulfate conjugates but not acetaminophen increased with obesity, whereas parent volume of distribution remained unchanged. Some rats raised on the energy-dense diet remained lean and were examined separately as a dietary control group. Acetaminophen disposition in these animals was indistinguishable from pellet-fed controls, suggesting that acetaminophen elimination changes in overweight animals resulted from obesity itself and not from the obesity inducing energy-dense diet. Although animals placed on the energy-dense diet ate fewer grams of food per day, their caloric intake was similar to that of pellet-fed animals when adjusted for differences in body weight and caloric content of the diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMedDate not supplied

Suppression of acetaminophen conjugation and of conjugate elimination in the rat by metyrapone, a classical P-450 inhibitor.

This study examined the effects of metyrapone on the overall elimination of acetaminophen and on the individual processes principally responsible for elimination, the formation of acetaminophen sulfate and glucuronide. Because acetaminophen pharmacokinetics are nonlinear above a threshold dose, experiments were designed to investigate acetaminophen elimination in the linear (30 mg/kg) and nonlinear (150 mg/kg) ranges to assess possible effects of metyrapone on conjugating enzymes and on cofactor availability. Prior treatment with 400 mg/kg metyrapone tartrate decreased total clearance of acetaminophen over 30% in the linear range (25.4 +/- 2.0 vs. 36.2 +/- 3.7 ml/min/kg in controls; p less than 0.01) and over 40% in the nonlinear range of disposition (4.42 +/- 1.07 vs 7.76 +/- 1.37 ml/min/kg in controls, p less than 0.01). Partial clearance to acetaminophen glucuronide was decreased by metyrapone in each dose range. Partial clearance to acetaminophen sulfate also declined in each dose range but statistically so only after 150 mg/kg. Metyrapone decreased the renal clearance of acetaminophen sulfate and glucuronide when these conjugates were formed in vivo after acetaminophen administration. However, metyrapone failed to impair the renal clearance of acetaminophen glucuronide when preformed metabolites were administered directly. The utility of metyrapone as a specific inhibitor of oxidative drug metabolism appears to be limited for drugs such as acetaminophen by concomitant inhibition of competing conjugation pathways, which account for the majority of drug elimination.

Acetaminophen↗
PubMedDate not supplied

Macromolecular binding in assessing drug and chemical-induced tissue lesions.

The general concepts that underlie the use of macromolecular binding in studies of chemical-induced tissue lesions are reviewed. Parameters for studying the formation of chemically reactive metabolites are discussed and the factors that alter the formation and covalent binding of reactive metabolites are selectively emphasized. Some of the experimental work that led to these concepts is presented.

Acetaminophen↗