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PubMed2006

Contrasting changes in phase I and phase II metabolism of acetaminophen in male mice pretreated with carbon tetrachloride.

Effect of carbon tetrachloride (CCl(4)) pretreatment on the biotransformation and elimination of acetaminophen were examined in male mice. A 24 hr initial dose of CCl(4) (0.05 ml/kg, intraperitioneally) reduced the induction of hepatotoxicity resulting from acetaminophen treatment (350 mg/kg, intraperitoneally) as determined by changes in serum alanine and aspartate aminotransferase, and sorbitol dehydrogenase activities. Acetaminophen and the major metabolites in plasma were monitored for 12 hr following acetaminophen treatment. CCl(4) pretreatment decreased the plasma concentrations of acetaminophen-cysteine and acetaminophen-mercapturate, but acetaminophen-glucuronide and acetaminophen-sulfate were increased significantly. The elimination of the parent drug from plasma was not affected by CCl(4). In urine collected for 24 hr, the concentrations of acetaminophen-sulfate and acetaminophen-glucuronide were increased by 84% and 33%, respectively, whilst acetaminophen-cysteine and acetaminophen-mercapturate were reduced to approximately one third of control. Expression of cytochrome P450 (CYP) isozymes was determined using antibodies of 2E1 and 1A2 as probes. CYP2E1 and 1A2 expressions were decreased significantly by CCl(4). Likewise, CCl(4) treatment reduced the microsomal p-nitrophenol hydroxylase and p-nitroanisole O-demethylase activities to less than one third of control. The results indicate that, although CCl(4) reduces the generation of thioether conjugates of acetaminophen by decreasing the CYP activities, inhibition of the oxidative metabolism of acetaminophen is counterbalanced by the enhancement of conjugate formation via the glucuronide and sulfate pathways, resulting in elimination of the drug at a rate equivalent to that in normal mice. It is suggested that liver injury in patients may not warrant a mandatory reduction of drug doses extensively inactivated via phase II reactions.

Acetaminophen↗

PubMed2006

Involvement of the multidrug resistance P-glycoprotein in acetaminophen-induced toxicity in hepatoma-derived HepG2 and Hep3B cells.

Acetaminophen overdose causes severe hepatic failure. Although the mechanisms of acetaminophen hepatotoxicity have been well investigated, little is known about the involvement of the P-glycoprotein in acetaminophen transport and toxicity. P-Glycoprotein is a membrane efflux pump, playing a significant role in regulating absorption, excretion, and tissue distribution of many drugs. To evaluate the contribution of P-glycoprotein transporter in the course of acetaminophen-induced toxicity, HepG2 and Hep3B cells with different P-glycoprotein expression and activity, were treated by acetaminophen (1-10 mM) for different time periods, with or without the P-glycoprotein inhibitor verapamil. P-Glycoprotein activity was determined by rhodamine 123 efflux assay and western blot analysis. To assess the acetaminophen-induced toxicity and effect of verapamil, we investigated cellular redox status, phosphatidylserine externalization, nuclear fragmentation and ultrastructural changes. Verapamil markedly enhanced acetaminophen-induced oxidative damage and cell death. Moreover, verapamil revealed acetaminophen toxicity even at subtoxic levels. High acetaminophen concentrations increased P-glycoprotein activity and content in both HepG2 and Hep3B cells. These observations suggest the involvement of P-glycoprotein in acetaminophen transport. Notwithstanding the differences of the investigated hepatoma cell lines in P-glycoprotein function, acetaminophen-induced toxicity was similar, possibly due to different functions of drug-metabolizing systems. We conclude that acetaminophen is a P-glycoprotein substrate and P-glycoprotein is involved in acetaminophen transport and toxicity in HepG2 and Hep3B cells. This study establishes the fact that acetaminophen can modulate P-glycoprotein in tumour cells, suggesting that its routine use in cancer patients in combination with anticancer drugs, may influence the result of chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

In vivo mechanisms of tissue-selective drug toxicity: effects of liver-specific knockout of the NADPH-cytochrome P450 reductase gene on acetaminophen toxicity in kidney, lung, and nasal mucosa.

Acetaminophen overdose causes toxicity in liver and extrahepatic tissues. Although it is well established that cytochrome P450 enzymes play a critical role in the metabolic activation of acetaminophen, it is not yet clear whether acetaminophen toxicity in extrahepatic tissues is a consequence of hepatic biotransformation. The aim of this study was to determine whether extrahepatic acetaminophen toxicity is altered in a mouse model that has liver-specific deletion of the NADPH-cytochrome P450 reductase (Cpr) gene. Liver-specific Cpr-null (Null) mice were resistant to acetaminophen hepatotoxicity, and they showed faster acetaminophen clearance than did wild-type mice at a toxic acetaminophen dose (400 mg/kg i.p.). However, when circulating acetaminophen levels were made equivalent in the two strains, the severity of extrahepatic acetaminophen toxicity was decreased in the Null relative to that in the wild-type mice in the lung, kidney, and lateral nasal glands, although not in the nasal olfactory and respiratory mucosa. In the lung and liver, the decreased acetaminophen toxicity was accompanied by substantial decreases in the formation of acetaminophen-protein adducts in the Null mice; adducts were not detected in other tissues examined. These results indicate that acetaminophen toxicity in the nasal mucosa is not dependent on hepatic microsomal P450-catalyzed metabolic activation and that acetaminophen toxicity in the lung, kidney, and lateral nasal glands is at least partly caused by liver-derived acetaminophen metabolites.

Acetaminophen↗

PubMed1984

Evaluation of activated charcoal-sodium sulfate combination for inhibition of acetaminophen absorption and repletion of inorganic sulfate.

Activated charcoal is an effective inhibitor of acetaminophen absorption while sodium sulfate can prevent the depletion of endogenous inorganic sulfate associated with the formation of acetaminophen sulfate. Administration of activated charcoal plus sodium sulfate soon after acetaminophen overdose may reduce acetaminophen absorption and facilitate the elimination of absorbed acetaminophen by providing sufficient sulfate ion for rapid sulfation of the drug. This investigation was designed to determine if sodium sulfate modifies the inhibitory effect of activated charcoal on acetaminophen absorption or if activated charcoal affects the absorption of sodium sulfate. Eight normal adults received, on separate occasions, 1 g acetaminophen, 1 g acetaminophen and 18 g sodium sulfate (decahydrate), 1 g acetaminophen with 10 g activated charcoal and 1 g acetaminophen, with 10 g activated charcoal and 18 g sodium sulfate, in random order. Urine was collected for 48 hours and assayed for acetaminophen and its major metabolites and for inorganic sulfate. The results confirm that activated charcoal can reduce acetaminophen absorption and show that oral administration of activated charcoal with sodium sulfate does not alter the inhibitory effect of activated charcoal on acetaminophen absorption or the bioavailability of the sulfate. A combination of activated charcoal and sodium sulfate may therefore be useful for the initial management of acetaminophen overdose.

Absorption↗

PubMedDate not supplied

Inhibition of acetaminophen sulfation by 2,6-dichloro-4-nitrophenol in the perfused rat liver preparation. Lack of a compensatory increase of glucuronidation.

The effectiveness of 2,6-dichloro-4-nitrophenol ( DCNP ) as an inhibitor of sulfation of acetaminophen, and the effect of DCNP on other conjugation reactions such as glucuronidation and glutathione conjugation were investigated in the once-through perfused rat liver preparation. The formation of glucuronide and glutathione conjugates of acetaminophen was insignificant under conditions when sulfation was suppressed either by the absence of inorganic sulfate or the presence of DCNP , suggesting that acetaminophen was a poor substrate for glucuronidation (high Km) and for the formation of the reactive metabolite leading to the formation of acetaminophen glutathione conjugate. DCNP was most effective in suppressing sulfation at low concentrations of acetaminophen, and the degree of inhibition increased with DCNP concentration, possibly due to a competitive mechanism of inhibition. Subsequent studies with tracer concentration of 3H-acetaminophen and 40 microM DCNP indicated that the steady state hepatic extraction ratio of acetaminophen decreased by 16%, sulfation was reduced by 19%, whereas glucuronidation increased by 28% in the presence of DCNP ; glutathione conjugation was not affected. Because acetaminophen is a poor substrate for glucuronidation and because glucuronidation remains a minor metabolic pathway in the biotransformation of acetaminophen, the changes in glucuronidation of acetaminophen with DCNP (28% above control value) failed to effect gross changes in acetaminophen disposition. Rather, the suppression of acetaminophen sulfation by DCNP is responsible for the decreased hepatic extraction of acetaminophen. This inhibition of acetaminophen sulfation by DCNP is readily reversible.

Acetaminophen↗

PubMed2003

Acetaminophen for osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis. Published guidelines and expert opinion are divided over the relative role of acetaminophen (also called paracetamol or Tylenol) and non-steroidal anti-inflammatory drugs (NSAIDs) as first-line pharmacologic therapy. The comparative safety of acetaminophen and NSAIDs is important to consider as NSAIDs have the potential for serious gastrointestinal, renal, and cardiovascular toxicities, and acetaminophen in high dosages (greater than or equal to 2 grams per day), may also have the potential for serious upper gastrointestinal toxicity. OBJECTIVES: To assess the efficacy and safety of acetaminophen versus placebo and versus NSAIDs (ibuprofen, arthrotec, celecoxib,naproxen, rofecoxib) for treating OA. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (Issue 3, 2002), MEDLINE (up to July 2002), and Current Contents (up to March 2002). Reference lists of identified RCTs and pertinent review articles were also hand searched. SELECTION CRITERIA: Published randomized controlled trials (RCTs) evaluating the efficacy and safety of acetaminophen alone in OA were considered for inclusion. DATA COLLECTION AND ANALYSIS: Pain, physical function and global assessment outcomes were reported. Results for continuous outcome measures were expressed as standardized mean differences. Dichotomous outcome measures were pooled using relative risk and the number needed to treat was calculated. MAIN RESULTS: Six RCTs and 1689 participants were included in the review. One study compared acetaminophen to placebo, and five compared acetaminophen to NSAIDs. In the placebo-controlled RCT, acetaminophen was shown to be clearly superior to placebo with a similar safety profile. The number needed to treat to achieve an improvement in pain was three. In the comparator-controlled RCTs, acetaminophen was less effective overall than NSAIDs in terms of pain reduction and global assessments but both drugs had similar efficacy in terms of improvements in functional status. No significant difference was found between the safety of acetaminophen and NSAIDs, although patients taking NSAIDS were more likely to withdraw due to GI events. REVIEWER'S CONCLUSIONS: The evidence to date suggests that NSAIDs are superior to acetaminophen for improving knee and hip pain in people with OA but have not been shown to be superior in improving function. The size of the treatment effect was modest, and the mean trial duration was only six weeks, therefore, additional considerations need to be factored in when making the decision between using acetaminophen or NSAIDs. In OA subjects with moderate-to-severe levels of pain, NSAIDs appear to be more effective than acetaminophen.

Acetaminophen↗

PubMed2006

Acetaminophen for osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis. Published guidelines and expert opinion are divided over the relative role of acetaminophen (also called paracetamol or Tylenol) and non-steroidal anti-inflammatory drugs (NSAIDs) as first-line pharmacologic therapy. The comparative safety of acetaminophen and NSAIDs is also important to consider. This update to the original 2003 review includes nine additional RCTs. OBJECTIVES: To assess the efficacy and safety of acetaminophen versus placebo and versus NSAIDs (ibuprofen, diclofenac, arthrotec, celecoxib, naproxen, rofecoxib) for treating OA. SEARCH STRATEGY: We searched MEDLINE (up to July 2005), EMBASE (2002-July 2005), Cochrane Central Register of Controlled Trials (CENTRAL), ACP Journal Club, DARE, Cochrane Database of Systematic Reviews (all from 1994 to July 2005). Reference lists of identified RCTs and pertinent review articles were also hand searched. SELECTION CRITERIA: Published randomized controlled trials (RCTs) evaluating the efficacy and safety of acetaminophen alone in OA were considered for inclusion. DATA COLLECTION AND ANALYSIS: Pain, physical function and global assessment outcomes were reported. Results for continuous outcome measures were expressed as standardized mean differences (SMD). Dichotomous outcome measures were pooled using relative risk (RR) and the number needed to treat (NNT) was calculated. MAIN RESULTS: Fifteen RCTs involving 5986 participants were included in this review. Seven RCTs compared acetaminophen to placebo and ten RCTs compared acetaminophen to NSAIDs. In the placebo-controlled RCTs, acetaminophen was superior to placebo in five of the seven RCTs and had a similar safety profile. Compared to placebo, a pooled analysis of five trials of overall pain using multiple methods demonstrated a statistically significant reduction in pain (SMD -0.13, 95% CI -0.22 to -0.04), which is of questionable clinical significance. The relative percent improvement from baseline was 5% with an absolute change of 4 points on a 0 to 100 scale. The NNT to achieve an improvement in pain ranged from 4 to 16. In the comparator-controlled RCTs, acetaminophen was less effective overall than NSAIDs in terms of pain reduction, global assessments and in terms of improvements in functional status. No significant difference was found overall between the safety of acetaminophen and NSAIDs, although patients taking traditional NSAIDS were more likely to experience an adverse GI event (RR 1.47, (95% CI 1.08 to 2.00). 19% of patients in the traditional NSAID group versus 13% in the acetaminophen group experienced an adverse GI event. However, the median trial duration was only 6 weeks and it is difficult to assess adverse outcomes in a relatively short time period. AUTHORS' CONCLUSIONS: The evidence to date suggests that NSAIDs are superior to acetaminophen for improving knee and hip pain in people with OA. The size of the treatment effect was modest, and the median trial duration was only six weeks, therefore, additional considerations need to be factored in when making the decision between using acetaminophen or NSAIDs. In OA subjects with moderate-to-severe levels of pain, NSAIDs appear to be more effective than acetaminophen.

Acetaminophen↗

PubMed2002

Determinants and sequelae associated with utilization of acetaminophen versus traditional nonsteroidal antiinflammatory drugs in an elderly population.

OBJECTIVE: Acetaminophen is recommended as initial therapy for patients with arthritis, particularly those at increased risk of nonsteroidal antiinflammatory drug (NSAID)-induced gastrointestinal (GI) side effects. However, higher doses of acetaminophen inhibit prostaglandin synthesis and have been associated with GI events. This study was undertaken to compare the observed and adjusted rates of GI events (hospitalizations, ulcers, dyspepsia, GI prophylaxis) occurring with higher versus lower doses of acetaminophen. METHODS: This was a retrospective cohort study of subjects ages >or=65 years who received a prescription for acetaminophen or NSAID between 1994 and 1996. Pharmaceutical and medical records were reviewed for 1 year of historical data prior to the index prescription of acetaminophen or non-aspirin NSAID. Risk factors for GI events were identified based on the historical data. To further control for bias, patients were categorized by propensity score (the likelihood of receiving acetaminophen, given defined risk factor values). Records were then reviewed for the duration of the index prescription or 30 days, whichever was less, to generate data on the occurrence of GI events. Determinants of acetaminophen utilization were identified using logistic regression, and rates of GI events for each therapy were examined using Poisson regression analyses, controlling for duration of exposure, individual risk factors, and propensity scores. RESULTS: The study included 26,978 patients in the NSAID cohort and 21,207 in the acetaminophen cohort. Determinants of acetaminophen utilization compared with NSAIDs (odds ratio [95% confidence interval]) included recent hospitalization (8.6 [7.7-9.5]), concomitant anticoagulation therapy (3.2 [2.7-3.8]), age >85 years (2.3 [2.1-2.4]), and history of prior GI events, especially those requiring hospitalization (14.6 [11.7-18.7]). Unadjusted rates of GI hospitalization, ulcer, and dyspepsia were higher for patients in the acetaminophen cohort than for those in the NSAID cohort. The occurrence of GI events in acetaminophen-treated patients was dose dependent, with rate ratios (compared with high-dose NSAIDs and adjusted for risk susceptibility) ranging from 0.6 (95% confidence interval 0.5-0.7) for 3,250 mg/day. CONCLUSION: In this cohort, acetaminophen utilization is more common in patients at higher risk of GI events. After adjustment for risk susceptibility, patients receiving higher doses of acetaminophen have higher rates of GI events compared with those receiving lower doses.

Acetaminophen↗

PubMed1999

Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species.

Hepatotoxic doses of acetaminophen to mice produce not only acetaminophen-protein adducts in the centrilobular cells of the liver, but nitrotyrosine-protein adducts in the same cells, the site of the necrosis. Nitration of tyrosine occurs with peroxynitrite, a species formed by reaction of nitric oxide (NO.) with superoxide (O2. -). Because NO. and O2.- may be produced by activated Kupffer cells and/or infiltrated macrophages, we pretreated mice with the macrophage inactivators/depeleters gadolinium chloride (7 mg/kg, intravenously [iv]) or dextran sulfate (10 mg/kg, iv) 24 hours before administration of acetaminophen (300 mg/kg). Mice treated with acetaminophen plus gadolinium chloride, or acetaminophen plus dextran sulfate, had significantly less evidence of hepatotoxicity as evidenced by lower serum alanine transaminase (ALT) levels (28 +/- 1 IU/L and 770 +/- 240 IU/L, respectively) at 8 hours compared with acetaminophen (6,380 +/- 408 IU/L). Analysis of hepatic homogenates for acetaminophen-protein adducts at 2 hours, a time of maximal covalent binding and before hepatocyte lysis, indicated that these pretreatments did not decrease covalent binding. Western blot analysis for the macrophage marker protein F4/80 in homogenates revealed not only the expected decrease by the macrophage inactivators/depleters, but also an apparent increase in acetaminophen-only-treated mice. At 8 hours nitrotyrosine-protein adducts were present in the acetaminophen-only-treated mice, but not in the acetaminophen plus gadolinium chloride-treated mice, or acetaminophen plus dextran sulfate-treated mice. High levels of heme-protein adducts, a measure of oxidative stress, were detected in livers of the 8 hour acetaminophen-only-treated mice. These data suggest that acetaminophen hepatotoxicity is mediated by an initial metabolic activation and covalent binding, and subsequent activation of macrophages to form O2.-, NO., and peroxynitrite. Nitration of tyrosine correlates with toxicity.

Acetaminophen↗

PubMed1992

Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome.

Gilbert's syndrome occurs in 5%-7% of the human population and is caused by an inherited deficiency in the glucuronidation of endogenous bilirubin, resulting in its accumulation and jaundice. The authors of the present study have previously shown that rats with a similar deficiency in bilirubin glucuronidation (Gunn rats) had reduced glucuronidation and enhanced susceptibility to the toxicity of the widely used analgesic, acetaminophen. Acetaminophen is eliminated primarily by glucuronidation, which prevents its cytochrome P-450-catalysed bioactivation to a hepatotoxic reactive intermediate. The purpose of this study was to determine whether people with Gilbert's syndrome had reduced glucuronidation and enhanced bioactivation of acetaminophen. Therefore, the biotransformation of acetaminophen, 20 mg/kg IV, was investigated in six subjects with Gilbert's syndrome (total bilirubin, 41 +/- 6 mumol/L; mean +/- SE) and six normal controls (total bilirubin, 11 +/- 2 mumol/L; P less than 0.01). Formation of the acetaminophen glucuronide conjugate measured by high-performance liquid chromatography was quantified by the ratio of the area under the plasma concentration-time curve (AUC) from 0 to 2 hours for the acetaminophen glucuronide divided by the AUC for acetaminophen. Acetaminophen bioactivation was quantified by the molar percentage of acetaminophen excreted in the urine during 24 hours as glutathione-derived conjugates (cysteine and mercapturic acid). Acetaminophen glucuronide formation in subjects with Gilbert's syndrome was 31% lower than that in normal controls (0.27 +/- 0.05 vs. 0.39 +/- 0.03; P less than 0.05), and bioactivation was 1.7-fold higher (3.5% +/- 0.4% vs. 2.1% +/- 0.3%; P less than 0.05). One control subject with normal bilirubin glucuronidation had substantially decreased acetaminophen glucuronide formation (0.20) and enhanced bioactivation (4.8%). Among all subjects, glucuronidation correlated inversely with bioactivation (r = -0.84; P less than 0.001), indicating that a decrease in a major pathway of elimination can shunt more drug through the toxifying route. Thus, a deficiency in bilirubin UDP-glucuronosyltransferase, evidenced by jaundice, can be paralleled by a deficiency in glucuronidation of other compounds. In these cases, jaundice can be a phenotypic determinant of enhanced acetaminophen bioactivation. On the other hand, some people with normal bilirubin glucuronidation may have a deficiency in the glucuronidation of acetaminophen; these people are not easily recognized.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetaminophen↗

PubMed1982

Platelet phenol sulfotransferase activity: correlation with sulfate conjugation of acetaminophen.

Human platelets contain two independently regulated forms of the drug conjugating enzyme, phenol sulfotransferase (PST). One form of platelet PST activity is relatively thermolabile (TL) and the other is relatively thermostable (TS). Acetaminophen is a substrate for both the TS and TL forms of PST. Our aim was to determine whether individual variations in platelet PST activity might reflect variations in teh sulfate conjugation of oral acetaminophen. Platelet PST activity was measured in blood samples from 29 randomly selected subjects. There was no significant correlation between the independently regulated activities of the TS and TL forms of PST in the platelets of these subjects (r = 0.16, P less than 0.4). Each of the 29 subjects ingested 10 mg/kg acetaminophen and 24-hr urinary excretions of acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate were measured. Average 24-hr urinary excretions of acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate were 2.3%, 46.9%, and 35.0% of the total dose of drug. There were significant correlations between the activities of both the TS and TL forms of platelet PST and the excretion of acetaminophen sulfate expressed as a percentage of the dose of the drug (r = 0.62, P less than 0.001; r = 0.456, P less than 0.02). The correlation coefficient between the TS activity and the excretion of acetaminophen sulfate was significant when the excretion of sulfate conjugate was expressed as a percentage of the sum of acetaminophen plus conjugated metabolites excreted (r = 0.565, P less than 0.002). Our data demonstrate that relative levels of platelet PST activity reflect individual variations in the urinary excretion of the sulfate conjugate of acetaminophen.

Acetaminophen↗

PubMed2001

Analgesic efficacy of rectal versus oral acetaminophen in children after major craniofacial surgery.

BACKGROUND: Analgesic acetaminophen (INN, paracetamol) plasma concentrations after major surgery in neonates and infants have not yet been established in the literature. We therefore conducted a study in our intensive care unit. METHODS: Forty children, mean (standard deviation) age, 10.3 (2.3) months, received 20 mg/kg acetaminophen either orally (n = 20) or rectally (n = 20) every 6 hours after a rectal loading dose (40 mg/kg) during elective craniofacial correction. Blood samples were taken 1 hour before and 2 hours after administration of acetaminophen maintenance doses; pain scores were obtained every 3 hours. RESULTS: Acetaminophen plasma concentrations were higher in patients receiving rectal acetaminophen (mean area under the concentration-time curve [AUC], 171.2 mg x h/L) than in patients receiving oral acetaminophen (mean AUC, 111.9 mg x h/L). Pain scores were higher in patients receiving oral acetaminophen. However, after exclusion of the patients who vomited from the group receiving oral acetaminophen, acetaminophen plasma concentrations and pain scores did not differ between the groups. There was no relation between acetaminophen plasma concentrations and pain scores. Although 9 of all 40 patients (22.5%) did not reach the expected analgesic acetaminophen plasma concentrations of 10- to 20 mg/L, <7.5% of the visual analog scale pain scores exceeded 4 cm, which was considered as a cutoff point. CONCLUSION: These are the first data showing that the analgesic acetaminophen plasma concentration after major surgery in this age group does not always reach the 10 to 20 mg/L level. These data also show that, after a rectal loading dose of 40 mg/kg has been given during surgery, the best way of administering acetaminophen after craniofacial surgery is the rectal route.

Acetaminophen↗

PubMed2005

Effect of ribose cysteine pretreatment on hepatic and renal acetaminophen metabolite formation and glutathione depletion.

Ribose cysteine (2(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)thiazolidine-4(R)-carboxylic acid) protects against acetaminophen-induced hepatic and renal toxicity. The mechanism for this protection is not known, but may involve inactivation of the toxic electrophile via enhancement of glutathione (GSH) biosynthesis. Therefore, the goal of this study was to determine if GSH biosynthesis was required for the ribose cysteine protection. Male CD-1 mice were injected with either acetaminophen or acetaminophen and ribose cysteine. The ribose cysteine cotreatment antagonized the acetaminophen-induced depletion of non-protein sulfhydryls in liver as well as GSH in kidney. Moreover, ribose cysteine cotreatment significantly increased the concentration of acetaminophen-cysteine, hepatic acetaminophen-mercapturate in liver and renal acetaminophen-GSH metabolites in kidney 4 hr after acetaminophen. To determine whether protection against acetaminophen-induced liver and kidney damage involved ribose cysteine dependent GSH biosynthesis, buthionine sulfoximine was used to selectively block gamma-glutamylcysteine synthetase (gamma-GCS). Plasma sorbitol dehydrogenase (SDH) activity and blood urea nitrogen from mice pretreated with buthionine sulfoximine and challenged with acetaminophen indicated that both liver and kidney injury had occurred. While co-treatment with ribose cysteine had previously protected against acetaminophen-induced liver and kidney injury, it did not diminish the acetaminophen-induced damage to either organ in the buthionine sulfoximine-treated mice. In conclusion, ribose cysteine serves as a cysteine prodrug that facilitates GSH biosynthesis and protects against acetaminophen-induced target organ toxicity.

Acetaminophen↗

PubMed2006

Retrospective analysis of transient elevations in alanine aminotransferase during long-term treatment with acetaminophen in osteoarthritis clinical trials.

BACKGROUND: In two recent osteoarthritis trials, alanine aminotransferase (ALT) elevations were observed more frequently in patients receiving acetaminophen 3.9 g daily than in patients receiving placebo, and the rates were higher than aminotransferase values observed in some previous osteoarthritis studies with acetaminophen. OBJECTIVE: To retrospectively analyze ALT data from McNeil osteoarthritis clinical studies involving acetaminophen in order to assess the frequency and magnitude of ALT elevations and rate of ALT resolution while patients remained on acetaminophen treatment. A review of the literature revealed a few reports of isolated aminotransferase elevations occurring during acetaminophen therapy, but these reports were not included in the analysis because they did not include enough information to evaluate the frequency, magnitude, and rate of ALT elevations while patients remained on acetaminophen treatment. RESEARCH DESIGN AND METHODS: Nine controlled clinical trials were identified in which at least one of the treatments was acetaminophen alone. Studies were included if patients had ALT and aspartate aminotransferase (AST) values obtained at baseline and an ALT value at an additional visit after initiating therapy. Seven studies met these criteria and were included in this analysis. In these studies, patients received acetaminophen 1950-4000 mg/day for 4 weeks up to 12 months. Laboratory testing was performed at weeks 0 and 4 in the three 4-week studies; at weeks 0, 2, 4, 8, and 12 in the two 12-week studies; at weeks 0, 1, 2, 4, 6, 8, and 13 in the 13-week study; and at months 0, 1, 3, 6, 9, and 12 in the 12-month study. The pooled data set consisted of patient demographics, dosing records, aminotransferase and bilirubin laboratory values, and adverse events. RESULTS: There were no reports of hepatotoxicity or hepatic failure in any acetaminophen-treated patient (n = 1530). In the seven studies, 1039 patients had both baseline AST and ALT activity < or = upper limit of the reference range and an on-treatment ALT measurement. While on long-term acetaminophen treatment, 181 of 1039 (17.4%) patients had an ALT value that exceeded the upper limit of the reference range. None of the 1039 patients had an on-treatment ALT level > 3 times upper limit of the reference range in conjunction with a serum bilirubin > upper limit of the reference range, and no patient had an ALT level > 10 times upper limit of the reference range. Of the 1039 patients, 44 (4.2%) had an on-treatment ALT level > 1.5 times upper limit of the reference range, and 31 of the 44 patients had a subsequent measurement of ALT. Of these 31 patients, 29 (93.5%) had documented resolution or decreasing ALT while on treatment. An ALT level > 1.5 times upper limit of the reference range was not associated with a higher frequency of symptoms potentially related to hepatic origin. LIMITATIONS: The studies included in this analysis were limited to McNeil studies, none of which were designed to specifically evaluate the patterns of ALT activity. Thus, the incidence of ALT elevations after any specific duration of dosing, and the temporal pattern of ALT elevations, cannot be accurately determined. In addition, methodological differences existed across the studies. CONCLUSION: This analysis involving > 1000 acetaminophen-treated patients shows that low-level, transient ALT elevations usually resolve or decrease with continued acetaminophen treatment, are unaccompanied by signs or symptoms of liver injury, and, as such, appear to be clinically insignificant. Maximum recommended daily doses of acetaminophen did not cause liver failure or dysfunction.

Acetaminophen↗

PubMed2006

Detection of acetaminophen protein adducts in children with acute liver failure of indeterminate cause.

OBJECTIVE: Acetaminophen cysteine protein adducts are a widely recognized correlate of acetaminophen-mediated hepatic injury in laboratory animals. The objective of this study was to use a new assay for the detection of acetaminophen cysteine protein adducts in children with acute liver failure to determine the role of acetaminophen toxicity in acute liver failure of unknown cause. METHODS: Serum samples from children with acute liver failure were measured for acetaminophen cysteine protein adducts using high-performance liquid chromatography with electrochemical detection. For comparison, samples from children with well-characterized acetaminophen toxicity and children with known other causes of acute liver failure also were measured for acetaminophen cysteine protein adducts. The analytical laboratory was blinded to patient diagnoses. RESULTS: Acetaminophen cysteine protein adduct was detected in 90% of samples from children with acute liver failure that was attributed to acetaminophen toxicity, 12.5% of samples from children with acute liver failure of indeterminate cause, and 9.6% of samples from children with acute liver failure that was attributed to other causes. Adduct-positive patients from the indeterminate cause subgroup had higher levels of serum aspartate aminotransferase and alanine aminotransferase and lower levels of bilirubin. Adduct-positive patients also had lower rates of transplantation and higher rates of spontaneous remission. CONCLUSIONS: A small but significant percentage of children with acute liver failure of indeterminate cause tested positive for acetaminophen cysteine protein adducts, strongly suggesting acetaminophen toxicity as the cause of acute liver failure. An assay for the detection of acetaminophen cysteine protein adducts can aid the diagnosis of acetaminophen-related liver injury in children.

Acetaminophen↗

PubMed1999

Metallothionein-I/II knockout mice are sensitive to acetaminophen-induced hepatotoxicity.

The purpose of this study was to examine whether intracellular metallothionein (MT) protects against acetaminophen hepatotoxicity. MT-I/II knockout (MT-null) and control mice were given acetaminophen (150-500 mg/kg i.p.), and liver injury was assessed 24 h later. MT-null mice were more susceptible than controls to acetaminophen-induced lethality and hepatotoxicity, as evidenced by elevated serum enzyme activities and histopathology. Zinc pretreatment, a method of MT induction, protected against acetaminophen hepatotoxicity in control mice, but not in MT-null mice. The susceptibility of MT-null mice to acetaminophen hepatotoxicity was not due to the increased acetaminophen bioactivation, as cytochrome P-450 enzymes, and acetaminophen-reactive metabolites in bile and urine were not increased in MT-null mice. Western blots of liver cytosol indicated that acetaminophen covalent binding at 4 h increased with acetaminophen dose, but there was no consistent difference between control and MT-null mice. Acetaminophen injection depleted cellular glutathione similarly in both control and MT-null mice, but produced more lipid peroxidation in MT-null mice, as evidenced by the abundance of thiobarbiturate-reactive substances, and by immunohistochemical localization of 4-hydroxynonenal and malondialdehyde protein adducts. MT-null hepatocytes were more susceptible than control cells to oxidative stress and cytotoxicity produced by N-acetylbenzoquinoneimine, a reactive metabolite of acetaminophen, as determined by oxidation of 2', 7'-dichlorofluorescin diacetate and lactate dehydrogenase leakage. In summary, this study demonstrated that MT deficiency renders animals more vulnerable to acetaminophen-induced hepatotoxicity. The increased sensitivity does not appear to be due to increased acetaminophen activation, glutathione depletion, or covalent binding, but appears to be associated with the antioxidant role of MT.

Acetaminophen↗

PubMed1986

Effect of prevention of inorganic sulfate depletion on the pharmacokinetics of acetaminophen in rats.

The elimination of large doses of acetaminophen is associated with substantial depletion of endogenous inorganic sulfate which is utilized for the formation of acetaminophen sulfate. This depletion has pronounced dose- and time-dependent effects on the pharmacokinetics of acetaminophen. The purposes of this investigation were to determine the pharmacokinetics of acetaminophen in rats when endogenous sulfate depletion is prevented by administration of inorganic sulfate and to develop a simple, physiologically based pharmacokinetic model for the elimination of acetaminophen under these conditions. Adult Sprague-Dawley rats received an i.v. injection and a continuous infusion of sodium sulfate as well as an i.v. injection of acetaminophen, either 15, 30, 150 or 300 mg/kg. Serum inorganic sulfate concentrations remained at or above the physiologic level at all times. Plasma concentrations of acetaminophen declined exponentially with time after the two lower doses but exhibited initial downward curvature in log-linear plots after the two larger doses. The time-averaged plasma clearance of acetaminophen decreased with increasing dose whereas the terminal half-life was dose-independent. Most of the drug was eliminated in the urine as acetaminophen sulfate but the dose fractions of acetaminophen glucuronide and unmetabolized drug excreted in the urine increased with increasing dose. The renal clearance of acetaminophen did not exhibit dose-dependence but the apparent formation clearance of acetaminophen glucuronide tended to decrease with increasing dose. The formation of acetaminophen sulfate is describable by Michaelis-Menten kinetics, with a Vmax of about 6.5 mumol/min/kg and an in vivo KM (referenced to plasma) of about 100 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗

PubMed1996

Acetaminophen-induced hepatotoxicity. Analysis of total covalent binding vs. specific binding to cysteine.

Acetaminophen-induced hepatotoxicity is believed to be mediated by covalent binding of the reactive metabolite N-acetyl-p-benzoquinone imine to essential proteins in liver. It has been shown that the primary reaction of this metabolite with hepatic proteins is the formation of 3-(cysteine-S-yl)-acetaminophen adducts. The importance of covalent binding to other amino acids that may be formed by reaction of N-acetyl-p-benzoquinone imine with protein is unclear. Previously, we developed immunochemical assays for the acetaminophen cysteine adducts by immunizing animals with the conjugate 3-(N-acetylcystein-S-yl)acetaminophen-keyhole limpet hemocyanin, wherein the carboxyl group of the N-acetyl-cysteine moiety was coupled to amino groups on the protein. A very sensitive and specific immunochemical assay was developed for acetaminophen specifically bound to cysteine groups on protein [3-(cystein-S-yl)acetaminophen protein adducts]. Analysis of protein adducts indicated that after toxic doses, acetaminophen covalently bound at high levels to cysteine residues on a relatively small number of hepatic proteins. In the present work, a new antiacetaminophen antiserum was prepared by immunizing mice with 4-acetamidobenzoic acid coupled to keyhole limpet hemocyanin. Competitive ELISA data indicate that the resulting antiserum has excellent recognition of acetaminophen and related arylacetamide derivatives. Using this new antiserum, Western blot analyses of liver proteins from acetaminophen-intoxicated mouse livers were performed and compared with similar assays using the anti-3-(cystein-S-yl)acetaminophen antiserum. Visual and densitometric analyses of the Western blots indicate that the two antisera detect the same primary acetaminophen protein adducts; however, minor differences in the intensity of certain bands were observed. These differences may represent either differences in antibody accessibility to 3-(cystein-S-yl)acetaminophen adducts or differences in the proportion of acetaminophen bound to cysteine vs. binding to other amino acids.

Acetaminophen↗