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PubMed2006

Defensive nature of Sargassum polycystum (Brown alga) against acetaminophen-induced toxic hepatitis in rats: role of drug metabolizing microsomal enzyme system, tumor necrosis factor-alpha and fate of liver cell structural integrity.

AIM: To assess the defensive nature of Sargassum polycystum (S. polycystum) (Brown alga) against acetaminophen (AAP)-induced changes in drug metabolizing microsomal enzyme system, tumor necrosis factor (TNF-alpha) and fine structural features of the liver during toxic hepatitis in rats. METHODS: Male albino Wistar strain rats used for the study were randomly categorized into 4 groups. Group I consisted of normal control rats fed with standard diet. Group II rats were administered with acetaminophen (800 mg/kg body weight, intraperitoneally). Group III rats were pre-treated with S. polycystum extract alone. Group IV rats were orally pre-treated with S. polycystum extract (200 mg/kg body weight for 21 d) prior to acetaminophen induction (800 mg/kg body weight, intraperitoneally). Serum separated and liver was excised and microsomal fraction was isolated for assaying cytochrome P450, NADPH Cyt P450 reductase and b(5). Serum TNF-alpha was detected using ELISA. Fine structural features of liver were examined by transmission electron microscopy. RESULTS: Rats intoxicated with acetaminophen showed considerable impairment in the activities of drug metabolizing microsomal enzymes, such as cytochrome P450, NADPH Cyt P450 reductase and b(5) when compared with the control rats. The rats intoxicated with acetaminophen also significantly triggered serum TNF-alpha when compared with the control rats. These severe alterations in the drug metabolizing enzymes were appreciably prevented in the rats pretreated with S. polycystum. The rats pretreated with S. polycystum showed considerable inhibition in the elevation of TNF-alpha compared to the rats intoxicated with acetaminophen. The electron microscopic observation showed considerable loss of structural integrity of the endoplasmic reticulum, lipid infiltration and ballooning of mitochondria in the acetaminophen-intoxicated rats, whereas the rats treated with S. polycystum showed considerable protection against acetaminophen-induced alterations in structural integrity. CONCLUSION: These observations suggest that the animals treated with S. polycystum extract may have the ability to protect the drug metabolizing enzyme system and mitochondrial functional status from free radical attack, thereby showing its defense mechanism in protecting hepatic cells from acetaminophen toxic metabolite N-acetyl-para-benzoquinone-imine (NAPQI).

Acetaminophen↗
PubMed2004

Glucuronidation of acetaminophen is independent of UGT1A1 promotor genotype.

The metabolism of acetaminophen (paracetamol) is thought to be altered in patients with Gilbert's syndrome (GS), a chronic unconjugated hyperbilirubinemia. The underlying cause of GS is a polymorphism in the promotor region of the uridine diphosphate glucuronosyltransferase isoform 1A1 gene (UGT1A1*28), its encoded enzyme being responsible for the glucuronidation of bilirubin and presumably acetaminophen. Decreased enzyme activity results in elevated bilirubin levels and may activate various metabolic pathways leading to higher amounts of potentially hepatotoxic acetaminophen metabolites. Patients with GS might be more susceptible to unexpected side effects while taking acetaminophen and other drugs which are substrates of UGT1A1. The possibility of a correlation between glucuronidation capacity with respect to acetaminophen, UGT1A1 promotor polymorphism and the bilirubin serum level were investigated in 23 healthy male volunteers selected for UGT1A1 genotype (6 wildtypes, 9 mutants and 8 heterozygotes). One gram acetaminophen was administered p.o. and urine was collected over 2 4-hour periods. Unchanged acetaminophen and its glucuronide metabolite were determined using HPLC. The metabolic ratios unchanged acetaminophen/acetaminophen glucuronide in UGT1A1-wildtypes, heterozygotes and mutants showed no statistically significant differences. An association between metabolic ratio and serum bilirubin level could not be detected in any of the urine collection periods. These data confirm that there is no correlation between the capacity to glucuronidate acetaminophen, the UGT1A1 genotype and the bilirubin serum level. Acetaminophen is likely to be substrate of a UGT isoform other than the UGT1A1.

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PubMed2000

Preference for nonsteroidal antiinflammatory drugs versus acetaminophen and concomitant use of both types of drugs in patients with osteoarthritis.

OBJECTIVE: To analyze results of treatment of osteoarthritis (OA) with acetaminophen and the nonsteroidal antiinflammatory drugs (NSAID) through a patient survey. METHODS: A 15 minute telephone survey was conducted with 300 patients, including 172 with confirmed OA. RESULTS: Twenty-four percent of patients who took acetaminophen rated it as "very helpful," compared to 31% for ibuprofen, 30% for naproxen, and 56% for diclofenac. Drug continuation beyond 24 months was reported by 33% of patients for acetaminophen, 21% for ibuprofen, 17% for naproxen, and 19% for diclofenac. Acetaminophen was significantly less likely to be discontinued because of toxicity than NSAID. Patients who indicated that they would not take a drug again, and therefore be unlikely to participate in a clinical trial involving this drug, were 26% for acetaminophen, 40% for ibuprofen, 38% for naproxen, and 28% for diclofenac. About 30% of patients who took acetaminophen reported concurrent use of ibuprofen, naproxen, or diclofenac. Among the 67% of patients who identified a drug as "most helpful," 80% named an NSAID, compared to 20% who named acetaminophen or another analgesic as the "most helpful" drug. CONCLUSION: Patients take many different drugs for OA, most of which are not continued beyond 2 years. Many patients take both acetaminophen and an NSAID. Most patients who identified a drug as "most helpful" named an NSAID rather than acetaminophen or an analgesic drug. These findings may be of value in further development of management strategies and guidelines for OA.

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PubMed2000

Pharmacokinetics of acetaminophen and ibuprofen when coadministered with telmisartan in healthy volunteers.

Two open-label, two-way, crossover studies were performed to assess any pharmacokinetic interaction of telmisartan with either acetaminophen or ibuprofen. Healthy male adult volunteers (n = 12) received a single oral dose of acetaminophen 1 g alone and with oral telmisartan 120 mg in one study. Oral ibuprofen 400 mg three times daily with and without oral once-daily telmisartan 120 mg was given for 7 days in the other study conducted in 6 males and 6 females. In both studies, there was a washout period of > or = 13 days between single and combination medication administration. The primary end points Cmax and AUC were compared between combination (acetaminophen or ibuprofen + telmisartan) and single-agent medication (acetaminophen or ibuprofen). Pharmacokinetic drug interaction was assessed by analysis of variance (ANOVA) and calculation of 90% confidence intervals (CI) for treatment ratios using log-transformed parameters. Bioequivalence (i.e., lack of interaction) was concluded if the 90% CI of the ratios for both Cmax and AUC were within the acceptance limit of 0.80 to 1.25. Geometric mean Cmax values for acetaminophen and R-(-)- and S-(+)-ibuprofen enantiomers were similar with and without telmisartan coadministration (12.6 micrograms/mL vs. 14.1 micrograms/mL; 17.3 micrograms/mL vs. 16.7 micrograms/mL; 19.4 micrograms/mL vs. 19.5 micrograms/mL, respectively), and values for R-(-)- as well as S-(+)-ibuprofen were bioequivalent. Geometric mean AUC values for acetaminophen and R-(-)- and S-(+)-ibuprofen were also bioequivalent with and without telmisartan. The distribution and elimination parameters of both acetaminophen and ibuprofen were comparable in the presence or absence of telmisartan. The concomitant and single-agent medications were all well tolerated. In conclusion, the long half-life and excellent safety profile of telmisartan were unaffected by concurrent acetaminophen or ibuprofen medication; thus, once-daily dosing of telmisartan can be maintained, which may help to optimize patient compliance, and patients may self-administer concomitant acetaminophen or ibuprofen.

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PubMed2003

The difficulty of risk assessment for hepatic injury associated with supra-therapeutic acetaminophen use.

We examined historical and laboratory features to identify patients who do not experience hepatic injury when presenting with a history of repeated supra-therapeutic acetaminophen use by performing a retrospective, double cohort comparison over almost 5 y. One cohort included patients suffering severe hepatic injury after supra-therapeutic acetaminophen ingestion; the control cohort included all patients in a geographically limited population with repeated supra-therapeutic acetaminophen ingestion who did not experience severe hepatic injury. Demographics, baseline health, medications, ethanol consumption, acetaminophen dosage, reason for excessive acetaminophen dosing, acetaminophen concentration at presentation, presentation and peak hepatic enzymes, N-acetylcysteine (NAC) treatment, highest measured AST and outcome were abstracted from 1114 possible patient contacts. Twenty two of these met all inclusion criteria. Ten suffered severe hepatic injury, 12 did not. The actual acetaminophen dose consumed over a period of time was difficult to establish, but the historic quantity ingested exceeded 20 g in the majority of patients in both groups. High ethanol use was common in both groups. All patients who ultimately suffered severe liver injury presented with some injury. No patient who presented without some injury suffered severe injury. None of these patients were treated with NAC. Two patients who presented with minor injury (1 of whom received NAC), did not progress to severe injury. Future investigations of the cause of liver injury in patients exposed to supra-therapeutic doses of acetaminophen will require larger patient numbers. The lack of injury in similarly exposed patients underscores the peril of attempting to assess the role of risk factors without an appropriate control group. Our experience suggests history is unlikely to be clinically useful in predicting risk of injury. Future risk assessment studies should focus on objective presentation features like presence or absence of injury or serum acetaminophen levels.

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PubMed2004

Acute acetaminophen intoxication in Taiwan: outcomes and risk factors.

BACKGROUND AND PURPOSE: There is a paucity of information about acetaminophen intoxication from Taiwan. This study investigated the outcome and risk factors for acetaminophen-induced hepatotoxicity and validated the Rumack- Matthew nomogram in Taiwanese patients with acute acetaminophen intoxication. METHODS: A total of 75 patients with acetaminophen intoxication admitted through the emergency department were included in this retrospective analysis. Patients with a serum acetaminophen concentration above the possible risk line on the nomogram were treated with oral N-acetylcysteine. The primary outcome measure was the development of major hepatotoxicity, which was defined as a serum aminotransferase concentration greater than 1000 IU/L. Patient outcomes in the possible risk group and probable risk group were plotted on the modified Rumack-Matthew nomogram for validation. The risk factors for acetaminophen-induced hepatotoxicity were identified by multiple logistic regression analysis. RESULTS: No hepatotoxicity developed in patients with an initial acetaminophen concentration below the possible risk line on the nomogram. One out of 8 patients in the possible risk group developed major hepatotoxicity; 8 out of 22 patients in the probable risk group developed major hepatotoxicity, representing an incidence of 12.5% and 36.4%, respectively. Patients in the major hepatotoxicity group were older (32.5 vs 24.2 years, p = 0.019), and had a longer time to presentation (28.1 vs 6.7 hours, p < 0.01) than those in the non/minor hepatotoxicity group. Multiple logistic regression revealed that age and time to presentation were independent risk factors for hepatotoxicity (p = 0.033 and p = 0.002, respectively). CONCLUSIONS: The results of outcome analysis confirm that the modified Rumack-Matthew nomogram has a high sensitivity for identifying Taiwanese patients at risk for acetaminophen-induced hepatoxicity. Patient age and time to presentation were independent risk factors for acetaminophen-induced hepatotoxicity.

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PubMed2005

Efficacy of rofecoxib, celecoxib, and acetaminophen in patients with osteoarthritis of the knee. A combined analysis of the VACT studies.

OBJECTIVE: To compare efficacy among 1578 patients with osteoarthritis randomized to take acetaminophen 4000 mg (n=269), celecoxib 200 mg (n=523), rofecoxib 12.5 mg (n=259), or rofecoxib 25 mg (n=527) in a double blind trial [Vioxx, Acetaminophen, Celecoxib Trial (VACT2)]. Results were also pooled with the similarly designed VACT1 trial. METHODS: Patients evaluated over Days 1 to 6 and 6 weeks with Patient Global Assessment of Response to Therapy (PGART) and Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index. RESULTS: For VACT2, median time to good or excellent PGART response was 6, 5, 4, and 3 days for acetaminophen, celecoxib, rofecoxib 12.5 mg, and rofecoxib 25 mg (COX-2 inhibitors vs acetaminophen, p<or=0.035; rofecoxib 25 mg vs celecoxib, p=0.01). WOMAC response over the first 6 days was greater (p < 0.05) with both rofecoxib doses than acetaminophen and celecoxib. At Week 6, all COX-2 inhibitors provided significantly greater efficacy than acetaminophen. Good or excellent PGART was numerically, but not significantly, greater with rofecoxib 25 mg (55.4%) than celecoxib (50.6%) at Week 6; a significant difference was seen at Weeks 2 (6.9, p=0.022) and 4 (6.7, p=0.027) and over 6 weeks with analysis of all 5 PGART categories of response (p=0.035). Rofecoxib 25 mg provided greater response (p<0.05) than celecoxib on WOMAC subscales. Pooled analysis of VACT1/VACT2 demonstrated greater PGART (p=0.023) with rofecoxib 25 mg (56.1%) than celecoxib (49.8%) at 6 weeks and greater response to all other PGART and WOMAC endpoints, and confirmed superiority of COX-2 inhibitors to acetaminophen. Overall, tolerability of the study medications was generally good and similar. There was no significant difference between treatment groups in the percentage of patients who experienced a clinical adverse experience (AE). The incidence of discontinuations due to an AE was significantly lower with celecoxib (2.5%) compared to rofecoxib 25 mg (6.3%, p=0.004) or acetaminophen (7.8%, p< 0.001), and did not differ significantly from rofecoxib 12.5 mg (4.6%). Discontinuation rates due to edema and hypertension related AE were similar among all COX-2 inhibitors. CONCLUSION: Rofecoxib and celecoxib provided superior efficacy to acetaminophen. There was a more rapid and greater response with rofecoxib 25 mg than celecoxib 200 mg. Rofecoxib 12.5 mg demonstrated greater efficacy than celecoxib 200 mg over the first 6 days, and was similar over 6 weeks. All study medications were generally well tolerated.

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PubMed1990

Effect of beta-cyclodextrin on the in vitro permeation rate and in vivo rectal absorption of acetaminophen hydrogel preparations.

The amounts of beta-cyclodextrin and hydroxyl propyl methyl cellulose (HPMC) affecting the in vitro permeation rate of acetaminophen containing in both aqueous solutions and HPMC hydrogel preparations through the dialyzer tubing and isolated rat rectum were investigated. The partition coefficient of acetaminophen with or without beta-cyclodextrin in water/n-octanol system was also studied. In vivo absorption experiments of these test formulations were carried out by rectal administration in rats. The results indicate that the concentrations of beta-cyclodextrin and HPMC used decreased the amount permeated of acetaminophen from both test formulations. The more the amount of beta-cyclodextrin or HPMC the slower the permeation rate of acetaminophen. The permeation rate of acetaminophen through the dialyzer tubing was higher than that of acetaminophen through the isolated rat rectum. The result also shows beta-cyclodextrin and HPMC markedly reduced the in vivo bioavailability of acetaminophen from both test formulations. The lower partition coefficient and the higher hydrophilic properties of beta-cyclodextrin inclusion complex, and the higher viscosity of HPMC hydrogel matrix might be responsible for decreasing the in vitro permeation rate and depression of in vivo rectal absorption of acetaminophen. The in vitro permeation data was well correlated with in vivo absorption results, suggesting that the in vitro permeation study regardless of the dialyzer tubing method or the isolated rat rectum method might be used to estimate the in vivo rectal absorption of acetaminophen.

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PubMed1987

The 1- and 2-electron oxidation of acetaminophen catalyzed by prostaglandin H synthase.

Purified and microsomal preparations of prostaglandin H synthase catalyzed the arachidonic acid-dependent polymerization of acetaminophen and, in the presence of GSH, catalyzed the formation of 3-(glutathion-S-yl)acetaminophen. The formation of these products was inhibited by indomethacin and by purging reaction mixtures with argon. When H2O2 replaced arachidonic acid, neither indomethacin nor argon purging inhibited product formation. These results suggest that the peroxidase activity of prostaglandin H synthase catalyzed the oxidation of acetaminophen. Addition of GSH to reaction mixtures decreased acetaminophen polymerization; however, 3-(glutathion-S-yl)acetaminophen formation was maximal with 40 microM GSH, and higher concentrations of GSH did not substantially alter its formation. In the presence of GSH, either ascorbic acid or NADPH decreased polymerization by greater than 97% while 3-(glutathion-S-yl)acetaminophen formation was still observed. These data suggest that polymers and conjugates were formed by two different pathways. Since polymerization of acetaminophen involves radical termination of N-acetyl-p-benzosemiquinone imine whereas 3-(glutathion-S-yl)acetaminophen is formed by conjugation of N-acetyl-p-benzoquinone imine with GSH, the data suggest that prostaglandin H synthase catalyzed both the overall 1- and 2-electron oxidation of acetaminophen.

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PubMed1988

Deficiency in bilirubin UDP-glucuronyl transferase as a genetic determinant of acetaminophen toxicity.

Over 60% of the analgesic/antipyretic drug acetaminophen is eliminated by glucuronidation, which competes with a toxifying pathway involving cytochromes P-450-catalyzed bioactivation to a hepatotoxic reactive intermediate. A genetic deficiency of bilirubin UDP-glucuronyl transferase (GT) occurs in 5 to 7% of the population (Gilbert's disease, Crigler-Najjar syndrome) and this could predispose such people to acetaminophen hepatotoxicity. This hypothesis was evaluated in the homozygous Gunn rat, which is similarly deficient in GT, and the heterozygous Gunn rat, which has intermediary GT activity. Acetaminophen, 1 g/kg, was administered by gavage to animals 6 and 11 weeks of age, and age-matched Wistar rats as controls. Hepatic and renal cellular damage were assessed by respective increases in the peak plasma concentration of alanine aminotransferase and the blood urea nitrogen concentration, and confirmed by histological examination. Acetaminophen and metabolites were measured by high-performance liquid chromatography. Compared to Wistar controls, Gunn rats demonstrated up to a 110-fold greater hepatotoxic response to acetaminophen, with significantly lower production of the glucuronide conjugate and higher plasma concentrations of acetaminophen. Elevated acetaminophen concentrations correlated positively with both increased production of the acetaminophen-cysteine conjugate, reflecting bioactivation and hepatotoxicity. Older Gunn but not Wistar rats showed up to 26-fold more hepatotoxicity compared to their younger counterparts. In younger animals, heterozygotes demonstrated intermediary hepatotoxicity between homozygotes and Wistar controls. Hepatotoxicity was similar in the older heterozygotic and homozygotic Gunn rats, as was renal toxicity, which was enhanced 2- to 3-fold over controls. These results indicate that a genetic deficiency in bilirubin GT can be an important determinant of acetaminophen bioactivation and toxicity.

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PubMed1988

Mechanism by which ethanol diminishes the hepatotoxicity of acetaminophen.

The effect of 5 mM ethanol, maintained by a constant infusion, on the hepatotoxicity and disposition of acetaminophen was examined in 3-methylcholanthrene-induced rats. Ethanol infusion, which began 1 hr before acetaminophen and was maintained for 9 hr, resulted in a 2.8-fold higher hepatic glutathione concentration 6 hr after acetaminophen than did saline infusion. Ethanol infusion also diminished the rise in the 24 hr postacetaminophen plasma alanine transferase concentration by approximately 46%. Ethanol (5 mM) had only a modest effect on the oxidation of acetaminophen in rat liver microsomes, 7 to 14% inhibition over a range of acetaminophen concentration of 0.1 to 3 mM, whereas a 30 to 40% decline of covalent binding of acetaminophen-derived material was observed in vivo (peak acetaminophen concentration approximately 3 mM). Thus, a mechanism other than direct inhibition of cytochrome(s) P-450 by ethanol is invoked to account for the protective effect of ethanol. Ethanol infusion increased the ratio of total hepatocellular NADH/NAD+, and the ratio of free NADH/NAD+ in cytosol and mitochondria as a consequence of sequential oxidations of ethanol producing acetaldehyde and acetic acid in the respective compartments. The toxic electrophile produced by cytochrome P-450 oxidation of acetaminophen, N-acetyl-p-benzoquinoneimine, is reduced rapidly by NADH in aqueous solution. However, acetaminophen alone also increased free NADH/NAD+ in cytosol, and there was no indication that N-acetyl-p-benzoquinoneimine consumed NADH generated by the oxidation of ethanol. Ethanol infusion also increased the ratio of total hepatocellular NADPH/NADP+, apparently through transhydrogenation of NADP+ by NADH in mitochondria.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1987

Phenobarbital induction and acetaminophen hepatotoxicity: resistance in the obese Zucker rodent.

The obese Zucker rodent appears to lack a significant induction response after phenobarbital pretreatment. Induction of the hepatic cytochrome P-450 system with phenobarbital is known to enhance acetaminophen hepatotoxicity. The purpose of this study was to evaluate the influence of phenobarbital enzyme induction on acetaminophen hepatotoxicity in the obese and lean Zucker rodent. A preliminary study was performed evaluating the pharmacokinetics of acetaminophen in both the obese and lean Zucker rats. Data were utilized to calculate appropriate loading doses of acetaminophen during the subsequent hepatotoxicity study. Phenobarbital enzyme-inducing regimens were administered p.o. to achieve similar steady-state phenobarbital plasma concentrations. Control rats received appropriate placebo solutions. Serum hepatic transaminase enzymes and histologic evidence of hepatocellular necrosis were utilized to evaluate hepatic damage after p.o. administration of 1300 mg of acetaminophen to both obese and lean Zucker rats. Obese Zucker control animals had approximately 2.5 times the total hepatic glutathione content compared to their lean control (164.9 +/- 43.2 vs. 65.3 +/- 18.4 mumol/whole liver). Obese Zucker animals receiving only acetaminophen showed a trend toward a reduced incidence of hepatocellular necrosis compared to similarly treated lean littermates. Obese Zucker rodents pretreated with phenobarbital had an even more pronounced resistance to acetaminophen-induced hepatocellular necrosis (P less than .01) when compared to similarly treated lean littermates. Thus, acetaminophen hepatotoxicity is reduced in the obese Zucker rat and pretreatment with phenobarbital offers further protection against hepatocellular damage. We suggest that the previously unrecognized increase in hepatic glutathione plays a major role in the resistance of the obese Zucker rat to acetaminophen hepatotoxicity.

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PubMed1986

Role of glutathione turnover in drug sulfation: differential effects of diethylmaleate and buthionine sulfoximine on the pharmacokinetics of acetaminophen in the rat.

The purpose of this investigation was to examine the role of altered glutathione turnover in regulating sulfation. After diethylmaleate (3.9 mmol/kg i.p.) or buthionine sulfoximine (6 mmol/kg i.p.) injection, rats received an i.v. dose (30 or 150 mg/kg) of acetaminophen. Diethylmaleate pretreatment decreased the total clearance and increased the half-life of acetaminophen. The fraction of the dose recovered in the urine as acetaminophen sulfate and the partial metabolic clearance to acetaminophen sulfate were substantially diminished by diethylmaleate. Conversely, buthionine sulfoximine pretreatment increased the total clearance of acetaminophen and increased the partial metabolic clearance to acetaminophen sulfate. Diethylmaleate produces a prompt increase in glutathione turnover. This more rapidly uses available cysteine, the rate-limiting precursor of glutathione (and probably inorganic sulfate), thus limiting the availability of inorganic sulfate for sulfate conjugation. Importantly, diethylmaleate decreased the total clearance of acetaminophen and the partial clearance to acetaminophen sulfate at a dose of acetaminophen that does not produce complete sulfate depletion. This indicates that diethylmaleate may inhibit sulfation by mechanisms in addition to limiting sulfate availability. Buthionine sulfoximine selectively inhibits gamma-glutamylcysteine synthetase, thereby preventing cysteine utilization for glutathione resynthesis. Cysteine presumably becomes more available for oxidation to inorganic sulfate. These data suggest that glutathione is not normally converted to cysteine for further oxidation to sulfate when the latter endogenous ion is depleted.

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PubMed1986

Effects of cysteine pro-drugs on acetaminophen-induced hepatotoxicity.

The effects of three cysteine pro-drugs on the hepatotoxicity and biotransformation of acetaminophen were examined to evaluate the factors responsible for antidotal effectiveness. N-Acetyl-L-cysteine, L-2-oxothiazolidine-4-carboxylate or the L- or D-isomers of 2-methylthiazolidine-4-carboxylate were administered to male mice immediately after a hepatotoxic dosage of acetaminophen (5.0 mmol/kg). In general the antidotal efficacies and potencies of the L-cysteine pro-drugs were similar; 5.0 mmol/kg prevented hepatotoxicity whereas moderate and no protection were observed after 1.65 and 0.55 mmol/kg, respectively. In contrast, the D-isomer of 2-methylthiazolidine-4-carboxylate was ineffective at all dosages. Both L-2-oxothiazolidine-4-carboxylate and L-2-methylthiazolidine-4-carboxylate enhanced blood acetaminophen elimination (28-31% decrease in half-life) whereas N-acetyl-L-cysteine and D-2-methylthiazolidine-4-carboxylate did not. The L-cysteine pro-drugs increased the urinary excretion of the cysteine and mercapturic acid conjugates of acetaminophen (34-119%) but did not alter excretion of acetaminophen-glucuronide or acetaminophen-sulfate. The D-cysteine pro-drug did not affect the urinary excretion of the acetaminophen metabolites examined. Biochemical analyses of the phase II pathway co-substrates, i.e., UDP-glucuronic acid, adenosine 3'-phospho-5'-phosphosulfate and glutathione, were performed on liver samples from mice treated with pro-drugs and/or acetaminophen. The pro-drugs exhibited their greatest effect on hepatic glutathione concentrations. Treatment with L-cysteine pro-drugs decreased the extent of depletion and/or increased the rate of repletion of hepatic glutathione levels after acetaminophen administration.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1982

Influence of leukaemia on acetaminophen-induced hepatotoxicity in mice.

Since it is known that the metabolism of acetaminophen is involved in its hepatotoxicity and that drug metabolizing enzyme activity is decreased in tumor bearing animals, it was of interest to study the influence of L-1210 leukaemia on acetaminophen hepatotoxicity in BDF-1 male mice. A single oral dose of acetaminophen, 125 mg/kg, was given at the fifth day of the mice survival period (7.7 days) and the animals killed twenty-four hours later. As revealed by serum glutamic-pyruvic transaminase, serum glutamic-oxaloacetic transaminase and lactic dehydrogenase, acetaminophen was less hepatotoxic in leukaemic mice than in control mice by comparison with their own saline group; on the other hand the difference between control and leukaemic mice treated with acetaminophen was significant only for glutamic-pyruvic transaminase. Moreover, we found higher unchanged acetaminophen concentrations in plasma, liver, kidneys, brain and fat of the leukaemic mice as compared to controls, less conjugated metabolites in plasma and liver, decreased in vitro aniline hydroxylation and ethylmorphine N-demethylation. Finally, following acetaminophen administration, reduced hepatic glutathione was depleted to a much lesser extent in the tumor bearing animals than in controls. In conclusion, the L-1210 leukaemia seems to modify the acetaminophen hepatotoxicity and this effect might be explained by decreased acetaminophen biotransformation into toxic metabolites or intermediates.

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PubMed1981

Prevention of acetaminophen-induced hepatotoxicity by acute ethanol administration in the rat: comparison with carbon tetrachloride-induced hepatoxicity.

Acetaminophen-induced hepatotoxicity in the presence of ethanol has not been studied. To evaluate the effect of acute ethanol administration on the hepatoxicity of acetaminophen, young male Sprague-Dawley rats (b. wt. 90--130 g) were fasted for 18 hr and were given ethanol (6 g/kg p.o.) or saline. Six hours after this treatment, the rats were injected with acetaminophen (0.5--1.0 g/kg i.p.). In another group, rats were given ethanol (3 g/kg p.o.) or saline and acetaminophen (1 g/kg i.p.) concomitantly. In both groups, acetaminophen produced hepatic damage in saline controls, whereas ethanol treatment prevented the hepatoxicity as judged by serum enzyme activities, hepatic cytochrome P-450 content and liver histology. In 3-methylcholanthrene-treated animals, acetaminophen (0.25 g/kg)-induced hepatic damage was exacerbated, whereas again ethanol treatment (6 g/kg p.o.) apparently prevented the hepatotoxicity of acetaminophen. In contrast, carbon tetrachloride-induced hepatotoxicity (0.1--0.5 ml/kg i.p.) was markedly increased by acute ethanol administration 6 hr before the drug injection, suggesting that the interaction of ethanol- and drug-induced hepatotoxicity is complex. Because acetaminophen has been shown to produce hepatic injury after its biotransformation to reactive metabolite(s) by mixed-function oxidation, and because ethanol inhibits drug oxidation, it can be postulated that ethanol inhibits the biotransformation of acetaminophen to reactive metabolite(s) resulting in the prevention of hepatotoxicity.

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PubMed1978

Kidney metabolism of acetaminophen and phenacetin.

The metabolism of acetaminophen and phenacetin by rabbit kidney slices was investigated. Phenacetin, like aspirin, inhibited [131I] Hippuran accumulation by the organic acid transport system. Phenacetin exhibited a dose-dependent inhibition with a K1 of 0.5 mM; acetaminophen at concentrations as high as 1 mM did not alter organic acid transport. [3H] acetaminophen slice: media ratios of approximately 1 or less suggested that acetaminophen entered cortex and outer and inner medullary slices by diffusion rather than active transport. Approximately 95% of the acetaminophen within the slices readily diffused out into the media. The chromatographic patterns of this material were similar to that of the incubation media. The acetaminophen remaining within the slices was acid-precipitable and not extractable with organic solvents. This covalent binding of acetaminophen was inhibited by glutathione. More acetaminophen was bound in the renal medullar than cortex. These data suggest that the renal metabolism of acetaminophen observed in this in vitro study may be related to the nephritis observed in analgesic abuse.

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PubMed1995

Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen.

Acetaminophen is a mild analgesic and antipyretic agent that is safe and effective when taken in therapeutic doses. Ingestion of overdoses, however, may lead to acute liver failure accompanied by centrilobular degeneration and necrosis. Although the toxicity of acetaminophen is generally thought to be caused by direct interaction of its reactive metabolites with cellular macromolecules, recent studies have suggested that nonparenchymal cells also may contribute to tissue injury indirectly through the release of cytotoxic mediators. We analyzed the potential role of hepatic macrophages in acetaminophen hepatotoxicity by examining the effects of modulating the activity of these cells on tissue injury. Treatment of male Long Evans Hooded rats with acetaminophen (800 mg/kg) was found to induce extensive centrilobular hepatic necrosis. Pretreatment of the rats with either dextran sulfate or gadolinium chloride, two inhibitors of hepatic macrophage functioning, completely blocked hepatic necrosis, as well as increases in serum transaminase levels induced by acetaminophen. Interestingly, treatment of rats with the macrophage activator, lipopolysaccharide (LPS), also reduced tissue injury induced by acetaminophen. To exclude the possibility that the effects of gadolinium chloride, dextran sulfate, or LPS were due to alterations in acetaminophen metabolism, we analyzed the effects of these agents on various pharmacokinetic properties of this analgesic. Dextran sulfate and gadolinium chloride had no effect on the half-life of a low dose of acetaminophen (20 mg/kg), or on the activity of any of its individual pathways of metabolism, including the formation of acetaminophen-mercapturic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

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