Plasma Acetaminophen Concentration Research Articles

Plasma concentrations after high-dose (45 mg · kg−1) rectal acetaminophen in children

Although the recommended dose of rectal acetaminophen (25-30 mg.kg-1) is twice that for oral administration (10-15 mg.kg-1), the literature justifies the use of a higher dose when acetaminophen is administered via the rectal route. We measured venous plasma acetaminophen concentrations resulting from 45 mg.kg-1 of rectal acetaminophen in ten ASA 1, 15 kg paediatric patients undergoing minor surgery with a standardized anaesthetic. After induction of anaesthesia, a single 650 mg suppository (Abenol, SmithKline Beecham Pharma Inc.) was administered rectally. Plasma was sampled at t = 0, 15, 30, 45, 60, 90, 120, 180, 240 min in the first five patients and at t = 0, 30, 60, 90, 120, 180, 240, 300, 420 min in the subsequent five. Acetaminophen plasma concentrations were determined using a TDxFLx fluorescence polarization immunoassay (Abbott Laboratories, Toronto, Ontario). The maximum plasma concentration was 88 +/- 39 mumol.L-1 (13 +/- 6 micrograms.ml-1) and the time of peak plasma concentration was 198 +/- 70 min (mean +/- SD). At 420 min, the mean plasma concentration was 46 +/- 18 mumol.L-1 (7.0 +/- 0.9 micrograms.ml-1). No plasma concentrations associated with toxicity (> 800 mumol.L-1) were identified. A 45 mg.kg-1 rectal dose of acetaminophen resulted in peak plasma concentrations comparable with those resulting from 10-15 mg.kg-1 of oral acetaminophen at three hours after suppository insertion. It is concluded that the delayed and erratic absorption of acetaminophen after rectal administration leads to unpredictable plasma concentrations. Rectal acetaminophen will not be consistently effective for providing rapid onset of analgesia in children.

Evaluation of gastric emptying in severe, burn-injured patients.

The aim of this study was to evaluate the possible effect of a severe burn on gastric emptying by determining the absorption kinetics of orally administered acetaminophen. A prospective, controlled study. A ten-bed burn center in a 1,300-bed university hospital. Ten adult patients suffering from second-degree burn involving > 20% of total body surface area and 20 normal, healthy volunteers who acted as controls. Patients received routine treatment such as nutritional support and cimetidine. However, opiates were stopped for at least 12 hrs before the start of the study, and nonsteroidal anti-inflammatory drugs as alternatives were used. After an 8-hr fast, the subjects ingested 0.5 g acetaminophen with 200 mL of water. The plasma concentrations of acetaminophen were determined by high-performance liquid chromatography, and the absorption kinetics was estimated from determination of time to reach the maximum plasma concentration, the maximum plasma concentration, and the area under the plasma concentration-time curve. The mean time for reaching the maximum plasma concentration was 33 +/- 24 (SD) mins in patients and 39 +/- 24 mins in the healthy volunteers. The mean area under the plasma concentration-time curve from time 0 to 120 mins and the mean maximum plasma concentration were 556 +/- 190 micrograms/mL/min and 9.5 +/- 3.5 micrograms/mL in patients, and 539 +/- 131 micrograms/mL/min and 7.8 +/- 2.8 micrograms/mL in volunteers, respectively. There was no statistical difference between groups in the time to reach the maximum plasma concentration, the area under the plasma concentration-time curve from time 0 to 120 mins, and the maximum plasma concentration. The time for reaching the maximum plasma concentration was not correlated with the severity of the burn (% area of burn) and the duration of healing (days) after burn. We conclude that severe burn injury does not affect the kinetics of gastric emptying, and that 200 mL of water ingested 2 hrs before anesthesia is quite safe in severely burned patients. Also, the absorption kinetics of acetaminophen was not altered by burn injury.

Evaluating in vitro and in vivo the interference of ascorbate and acetaminophen on glucose detection by a needle-type glucose sensor

The aim of this work was to assess, in vitro and in vivo, the interference of ascorbate and acetaminophen on glucose measurements by a needle-type glucose sensor detecting hydrogen peroxide generated during the enzymatic oxidation of glucose, and to ascertain whether the protection against interference by the membranes used in the construction of the electrode is feasible. The oxidation of ascorbate and acetaminophen on a platinum electrode set at a 650 mV potential yielded a current representing 75 ± 5% and 25 ± 6% of that generated by the oxidation of an equimolar concentration of hydrogen peroxide, respectively. The bias introduced by the presence of 100 μmol l −1 ascorbate on the reading of 5 mmol l −1 glucose by the complete sensor (electrode + membranes) would be minimal (approximately 0.4 mmol l −1). By contrast, the bias introduced by 200 μmol l −1 of a acetaminophen (a plasma concentration easily reached in clinical practice) was about 7 mmol l −1. The sensor was implanted subcutaneously in anaesthetized rats ( n = 3). Using the current generated in the presence of a plasma acetaminophen concentration of about 200 μmol l −1) for glucose monitoring would lead to a major under-estimation (approx. 6 mmol l −1) of subcutaneous glucose concentrations.

Acetaminophen overdose: A 48-hour intravenous N-acetylcysteine treatment protocol

To determine the safety and efficacy of a 48-hour IV N-acetylcysteine (IV NAC) treatment protocol for acute acetaminophen overdose. Nonrandomized trial open to all eligible patients. Multicenter; hospitals included moderate- and high-volume private, university, and municipal hospitals in urban and suburban settings. Two hundred twenty-three patients were entered. Of these, 179 met inclusion criteria: acute acetaminophen overdose, plasma acetaminophen concentration above the treatment nomogram line, treatment with IV NAC according to the protocol, and sufficient data to determine outcome. IV NAC treatment consisted of a loading dose of 140 mg/kg followed by 12 doses of 70 mg/kg every four hours. Patients were grouped for analysis according to risk group based on the initial plasma acetaminophen concentration. Hepatotoxicity (aspartate aminotransferase or alanine aminotransferase of more than 1,000 IU/L) developed in 10% (five of 50) of patients at "probable risk" when IV NAC was started within ten hours of acetaminophen ingestion and in 27.1% (23 of 85) when therapy was begun after ten to 24 hours. Among "high-risk" patients first treated 16 to 24 hours after overdose, hepatotoxicity occurred in 57.9% (11 of 19). There were two deaths (two of 179, 1.1%). Adverse reactions resulting from NAC occurred in 32 of 223 cases (14.3%), consisting in 29 of 32 patients (91% of reactions) of transient, patchy, skin erythema or mild urticaria during the loading dose that did not require discontinuation of therapy. This 48-hour IV NAC protocol is safe and effective antidotal therapy for acetaminophen overdose. Based on available data, it is equal to 72-hour oral and 20-hour IV treatment protocols when started early and superior to the 20-hour IV regimen when treatment is delayed. Further study will be required to determine its relative efficacy in the high-risk patient treated very late.

Age-dependent changes in first-pass metabolism of acetaminophen in rats

The contribution of gastrointestinal tract (GIT), liver, and lung towards the first-pass metabolism of acetaminophen was examined using 3-week-old, 10-week-old and 1-year-old rats after administration of 30 mg kg-1 doses by intra-arterial, intravenous, intraperitoneal, and oral routes. Plasma concentrations of acetaminophen and its two major metabolites, acetaminophen glucuronide and acetaminophen sulfate, were measured for about 5h after drug administration. Total oral extraction of acetaminophen was extensive in 10-week-old and 1-year-old rats (Eo = 0.46) and the major contribution to the overall first-pass metabolism was due to the GIT (Eg = 0.50-0.53). Oral extraction in 3-week-old rats was minimal (Eo = 0.10) and there did not appear to be an extraction by the GIT (Eg = 0.00). These results suggest that the ability of GIT to metabolize acetaminophen to glucuronide and sulfate is undeveloped in the infant rats. No changes in the contribution of different organs to the first-pass metabolism of acetaminophen was observed 10 weeks after birth. Pharmacokinetic parameters for acetaminophen in infant rats (3-week-old) and 10-week-old rats were similar after drug administration by the intra-arterial and intravenous routes.

Fish oil protects mice against acetaminophen hepatotoxicity in vivo

Recent observations suggest that products of non-parenchymal liver cells such as eicosanoids and cytokines might play a role in the expression of liver injury after administration of acetaminophen and other noxious agents. We therefore investigated the effect of a fish oil diet, which results in the generation of eicosanoids with altered biological properties and suppresses the production of certain cytokines on acetaminophen hepatotoxicity. Mice were fed a diet with either 20% fish oil containing n-3 fatty acids or 20% olive oil containing n-6 fatty acids for 2 wk. Cytochrome P-450 activity and the concentration of glutathione were similar in the two groups before acetaminophen administration. Nevertheless, 24 hr after the administration of 375 mg/kg acetaminophen intraperitoneally, the extent of centrilobular necrosis and the activity of ALT in plasma were significantly lower in the n-3 fatty acid group (median = 277 vs. 3,367 IU/L; p less than 0.001). In the n-3 fatty acid group covalent binding of the drug to liver proteins (0.19 +/- 0.03 vs. 0.67 +/- 0.07 nmol/mg protein; p less than 0.01) and the median plasma concentration of acetaminophen (0.1 vs. 0.6 mmol/L) were significantly lower 3 hr after dosing. Mice fed the n-3 fatty acid diet excreted less acetaminophen sulfate but significantly more acetaminophen glucuronide in 24 hr. Thus the major protective effect of the fish oil diet appears to be an increased clearance of acetaminophen resulting from a stimulation of the glucuronidation of acetaminophen, which may be due to the fluidization of microsomal membranes by fish oil.

Fish oil protects mice against acetaminophen hepatotoxicity in vivo

Recent observations suggest that products of nonparenchymal liver cells such as eicosanoids and cytokines might play a role in the expression of liver injury after administration of acetaminophen and other noxious agents. We therefore investigated the effect of a fish oil diet, which results in the generation of eicosanoids with altered biological properties and suppresses the production of certain cytokines on acetaminophen hepatotoxicity. Mice were fed a diet with either 20% fish oil containing n-3 fatty acids or 20% olive oil containing n-6 fatty acids for 2 wk. Cytochrome P-450 activity and the concentration of glutathione were similar in the two groups before acetaminophen administration. Nevertheless, 24 hr after the administration of 375 mg/kg acetaminophen intraperitoneally, the extent of centrilobular necrosis and the activity of ALT in plasma were significantly lower in the n-3 fatty acid group (median = 277 vs. 3,367 IU/L; p < 0.001). In the n-3 fatty acid group covalent binding of the drug to liver proteins (0.19 ± 0.03 vs. 0.67 ± 0.07 nmol/mg protein; p < 0.01) and the median plasma concentration of acetaminophen (0.1 vs. 0.6 mmol/L) were significantly lower 3 hr after dosing. Mice fed the n-3 fatty acid diet excreted less acetaminophen sulfate but significantly more acetaminophen glucuronide in 24 hr. Thus the major protective effect of the fish oil diet appears to be an increased clearance of acetaminophen resulting from a stimulation of the glucuronidation of acetaminophen, which may be due to the fluidization of microsomal membranes by fish oil. (Hepatology 1991;13:557-561.)

Development of controlled release oral drug delivery system by membrane-coating method-I

In order to develop a controlled-release oral drug delivery system (DDS) which sustains the plasma acetaminophen (AAP) concentration for a certain period of time, microporous membrane-coated tablets were prepared and evaluatedin vitro. Firstly, highly water-soluble core tablets of AAP were prepared with various formulations by wet granulation and compression technique. Then the core tablets were coated with polyvinylchloride (PVC) in which micronized sucrose particles were dispersed. Effect of formula compositions of core tablets and coating suspensions on the pharmaceutical characteristics such as drug release kinetics and membrane stability of the coated tablets was investigatedin vitro. AAP was released from the coated tablets at a zero-order rate in a pH-independent manner. This independency of AAP release to pH change from 1.2 to 7.2 is favorable for the controlled oral drug delivery, since it will produce a constant drug release in the stomach and intestine regardless of the pH change in the GI tract. Drug release could be extended upto 10 h according to the coating condition. The release rate could be controlled by changing the formula compositions of the core tablets and coating suspensions, coat weight per each tablet, and especially PVC/sucrose ratio and particle size of the sucrose in the coating suspension. The coated tablets prepared in this study had a fairly good pharmaceutical characteristicsin vitro, however, overall evaluation of the coated tablets should awaitin vivo absorption study in man.

First‐pass metabolism of acetaminophen in rats after low and high doses

The first-pass metabolism of acetaminophen was examined in rats after the administration of 15, 30, 150, and 300 mg kg-1 doses by intra-arterial, intravenous, portal vein, and oral routes. Plasma concentrations of acetaminophen and its two major metabolites, acetaminophen glucuronide and acetaminophen sulfate, were measured for about 5 h after drug administration. The first-pass effect after oral administration (oral extraction) was extensive (Eo = 0.34-0.50) at all doses administered. Calculation of the relative contribution of the gastrointestinal tract, liver, and lung to the oral extraction of acetaminophen indicated that the major contribution was due to the gastrointestinal tract at all doses studied (Eg = 0.33-0.50). At higher doses (150 and 300 mg kg-1) clearance was lower possibly due to the saturation of acetaminophen sulfate formation. However, even at these high doses, the contribution of the gastrointestinal mucosa to the oral extraction remained unchanged. Therefore, it appears that the apparent dose-dependent characteristics of acetaminophen metabolism may be due to the saturation of acetaminophen sulfate formation in the liver.

Computer-assisted predictive mathematical relationship among plasma acetaminophen concentration and time and hepatotoxicity in man

A microcomputer program in BASIC for predicting hepatotoxicity in man resulting from a single overdosage ingestion of acetaminophen was designed. A formula used in this program is derived from the data reported by Prescott and his coworkers (Lancet i (1971) 519–522). Analysis of the actually reported and the computer-assisted predicted data has shown that the computer-assisted predictive formula may be clinically helpful in determining if the plasma acetaminophen level is in the toxic or nontoxic range.

Metabolic evidence for the involvement of enzymatic bioactivation in the cataractogenicity of acetaminophen in genetically susceptible ( [formula omitted]) and resistant ( [formula omitted]) murine strains

Acetaminophen has been shown to be cataractogenic in mice and rabbits. C57BL 6 and DBA 2 mice respectively are genetically susceptible and resistant to the induction of cytochrome P-448 by 3-methylcholanthrene (3-MC). This isoenzyme is thought to bioactivate acetaminophen to a toxic reactive intermediate. These two murine strains also are correspondingly susceptible and resistant to acetaminophen cataractogenesis. To evaluate the potential role of enzymatic bioactivation as a determinant of acetaminophen cataractogenesis, C57BL 6 and DBA 2 mice were treated with acetaminophen, 300 or 400 mg/kg intraperitoneally (ip), with or without pretreatment 48 hr earlier using 3-MC, 200 mg/kg ip. Lenticular cataracts were evaluated using the unaided eye and a slit lamp, and hepatotoxicity was evaluated by determination of peak plasma concentration of alanine aminotransferase (ALT). Plasma concentrations of acetaminophen and metabolites, particularly the glutathione (GSH)-derived conjugates (cysteine and mercapturic acid) reflecting enzymatic bioactivation, were measured by high-performance liquid chromatography. Cataracts developed only in C57BL 6 mice pretreated with 3-MC, occurring in 1 of 5 and 5 of 5 animals treated respectively with 300 and 400 mg/kg of acetaminophen. Comparing these two groups of induced C57BL 6 mice, production of the cysteine conjugate of acetaminophen was 2.5-fold higher with the 400 mg/kg dose of acetaminophen ( p < 0.05). Compared to their respective dose-matched, noninduced controls, cysteine conjugate production in the 300 and 400 mg/kg dose groups of induced C57BL 6 mice respectively was 3-fold and 4-fold higher ( p < 0.05). No DBA 2 mice developed cataracts. No mercapturic acid conjugate was detectable in the plasma of DBA 2 mice, and production of the cysteine conjugate was not altered in this strain by increasing the dose of acetaminophen or by pretreatment with 3-MC. The mean peak plasma concentration of the cysteine conjugate, reflecting acetaminophen bioactivation, was 5-fold higher in animals developing cataracts compared with those without cataracts ( p < 0.001). Plasma concentrations of unmetabolized acetaminophen were similar in all groups and unrelated to the development of cataracts. All mice of both strains pretreated with 3-MC showed evidence of hepatotoxicity, indicating a dissociation between hepatotoxic and cataractogenic susceptibility. The dependence of acetaminophen-induced cataracts upon P-448 induction, and the apparent obligatory relation between the elevation of GSH-derived metabolites and the development of cataracts, suggest that enzymatic bioactivation may be a critical determinant of acetaminophen cataractogenesis.

Ipecac-Induced Emesis and Reduction of Plasma Concentrations of Drugs Following Accidental Overdose in Children

Syrup of ipecac is widely used following accidental drug overdosage in children. Proof of its efficacy, however, in reducing the risk of poisoning is limited. We prospectively studied the effect of early v late induction of emesis by ipecac in 50 children younger than 5 years of age with accidental acetaminophen poisoning. The mean estimated ingested dose was 165 mg/kg, and all patients vomited within 15 to 255 (mean 78) minutes postingestion. Although the predicted four-hour plasma acetaminophen concentration was 97 +/- 4 micrograms/mL (mean +/- SEM, calculated on the basis of the estimated ingested dose), the measured four-hour plasma acetaminophen concentration was 34 +/- 5 micrograms/mL (P less than .01). To assess the efficacy of early v late ipecac-induced emesis, we used the ratio of measured to predicted four-hour acetaminophen plasma concentration. The ratio of the measured to predicted four-hour level increased as the delay in time to vomiting increased (r = .60, P less than .001). Ipecac syrup was administered more promptly when available in the home than when obtained from a pharmacy or a medical facility (26 +/- 8 v 83 +/- 13 minutes postingestion, respectively; P less than .001) and vomiting occurred earlier (49 +/- 9 v 103 +/- 12 minutes postingestion; P less than .01). Although the mean estimated doses ingested were greater in patients who received ipecac syrup at home, their four-hour plasma acetaminophen concentrations were lower. These data suggest that prompt administration of ipecac syrup results in a greater reduction in plasma acetaminophen concentrations in potentially toxic overdosages in children.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of delayed esophageal transit on acetaminophen absorption.

Twenty patients awaiting cardiac catheterization swallowed a single tablet containing acetaminophen and barium sulfate. The first 11 subjects swallowed the tablet while supine; its progress down the esophagus was followed by fluoroscopy. In 10 of these subjects, transit of the tablet was delayed in the esophagus. The other nine subjects swallowed the tablet while standing; it entered the stomach immediately. The plasma concentration profile of acetaminophen was measured in all subjects. When there was delayed esophageal transit of tablets, the initial absorption of acetaminophen (measured as the AUC over the first 60 min) was lower than that after normal esophageal transit of tablets. The peak plasma acetaminophen concentration was also lower and occurred on average 70 min later when transit was delayed. These kinetic changes decrease the effectiveness of acetaminophen as an analgesic. We recommend that, to ensure rapid and complete drug absorption, patients be advised to swallow tablets with a large amount of water while standing.

Gastric emptying in normal subjects and patients with peptic ulcer

Gastric emptying in patients with peptic ulcer and normal subjects was studied using the acetaminophen method. The subjects consisted of 15 normal subjects, 52 gastric ulcer patients and 65 duodenal ulcer patients, who were studied in active stage of the ulcer. As an indicator of gastric emptying, the plasma acetaminophen concentration was measured by dye method (diphenylhydrazyl), as mcg/ml, at 45 minutes after ingestion of a high calory pasty test meal (200 ml) with 1.5 gr of acetaminophen. In normal subjects, the plasma acetaminophen concentration was 9.4 +/- 3.6 mcg/ml. In gastric ulcer patients, the concentration was 7.4 +/- 3.2 mcg/ml, which showed significantly delayed gastric emptying (P less than 0.05). In duodenal ulcer patients, the concentration was 11.6+/-3.3 mcg/ml, which suggested significantly rapid gastric emptying (P less than 0.05). In consideration of gastric secretion, gastric ulcer cases with lower acid secretion have more delayed gastric emptying. In duodenal ulcer cases with hypersecretion, gastric emptying is more rapid than normo-and/or hyposecretory cases (P less than 0.005). The delayed gastric emptying may play a role in etiology of gastric ulcer. On the other hand, the rapid gastric emptying with gastric acid hypersecretion may be important in the pathogenesis of duodenal ulcer.

Acetaminophen: Report of an Unusual Poisoning

This is a report of an unusual acetaminophen poisoning in a 3-year-old girl who, three days after the ingestion of an estimated thirty-five 325-mg tablets of acetaminophen, had the highest levels of hepatic enzymes ever recorded at Duke Hospital. Although she was only moderately ill with an enlarged liver, she was discharged from the hospital on the seventh day in good condition. The liver enzyme levels returned to normal when last assessed, 50 days after ingestion. The importance of determining acetaminophen plasma concentration at different times to evaluate more precisely the plasma half-life is discussed, along with the current suggested therapy now being recommended for acetaminophen poisoning.