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PubMed2003

Efficacy and safety of clemastine-pseudoephedrine-acetaminophen versus pseudoephedrine-acetaminophen in the treatment of seasonal allergic rhinitis in a 1-day, placebo-controlled park study.

BACKGROUND: Allergic rhinitis afflicts more than 40 million people in the United States and is a leading cause of reduced productivity at work and in school. Patients with allergic rhinitis have a wide range of symptoms that are often treated with oral combination products that contain antihistamines, decongestants, and analgesics. OBJECTIVE: To evaluate the onset of action and the extent of efficacy and safety of a combination (CPA) of clemastine (0.68 mg), pseudoephedrine (60 mg), and acetaminophen (1,000 mg) versus a combination (PA) of pseudoephedrine and acetaminophen versus placebo in the treatment of seasonal allergic rhinitis (SAR). The primary goal was to evaluate the benefit of adding clemastine to the PA combination product to treat the symptoms of SAR. METHOD: A 1-day, multicenter, double-blind, double-dummy, randomized, parallel-group park study was organized, and medication was given at 9:00 AM and 3:00 PM. RESULTS: A total of 298 subjects participated at two outdoor facilities. The primary efficacy outcome was the major symptom complex score averaged over the period of 2 to 5 hours after each dose. Mean absolute and percentage reduction in major symptom complex averaged over the period of 2 to 5 hours in the CPA group was significantly superior to those of either the PA (P < 0.01) or placebo (P < 0.03) groups. Somnolence, fatigue, and nausea were the most common volunteered adverse events; only somnolence was significantly greater after CPA than after either PA or placebo. CONCLUSIONS: Treatment with CPA was safe and highly effective in reducing symptoms associated with SAR. It was more effective than either PA or placebo over most of the postdose observation period.

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PubMed1997

Biopharmaceutical studies on drug/conjugated-metabolite interactions. III. Effect of acetaminophen sulfate and its positional isomers on the pharmacokinetics of acetaminophen in rats.

The effect of three positional isomers, o-, m- and p-acetylaminophenyl sulfate (AOAPS, AMAPS and APAPS (acetaminophen sulfate), respectively), on the pharmacokinetics of acetaminophen (APAP) was investigated in rats. All of the intravenously administered positional isomers were rapidly eliminated from plasma, and approximately 80% of the dose was excreted in an unchanged form in the urine within 4 h, while biliary excretions represented a small percent of the doses. Following the intravenous bolus injection of APAP, plasma elimination of APAP was accelerated and the distribution volume of APAP was increased under a steady state concentration (about 10 microg APAP eq/ml) of AOAPS or APAPS, but not AMAPS, as compared with saline infusion. Total body clearances of APAP were increased from 18.3 ml/min/kg for the control to 23.9 and 26.9 ml/min/kg for AOAPS and APAPS coadministration, respectively. AOAPS and APAPS competitively displaced the serum protein binding of APAP, while AMAPS had little effect. The distribution volume of unbound APAP was anomalously increased by APAPS, while it was not affected by AOAPS or AMAPS. Tissue-to-plasma concentration ratios of APAP were significantly increased by APAPS in the liver, kidney and brain, while they were only slightly increased by AOAPS. It was suggested that APAPS has not only the displacing activity of serum protein binding but also other specific effectiveness on the distribution of APAP.

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PubMed1991

Immunohistochemical localization and quantification of the 3-(cystein-S-yl)-acetaminophen protein adduct in acetaminophen hepatotoxicity.

Acetaminophen overdose causes severe hepatotoxicity in humans and laboratory animals, presumably by metabolism to N-acetyl-p-benzoquinone imine: and binding to cysteine groups as 3-(cystein-S-yl)acetaminophen-protein adduct. Antiserum specific for the adduct was used immunohistochemically to demonstrate the formation, distribution, and concentration of this specific adduct in livers of treated mice and was correlated with cell injury as a function of dose and time. Within the liver lobule, immunohistochemically demonstrable adduct occurred in a temporally progressive, central-to-peripheral pattern. There was concordance between immunohistochemical staining and quantification of the adduct in hepatic 10,000g supernate, using a quantitative particle concentration fluorescence immunoassay. Findings include: 1) immunochemically detectable adduct before the appearance of centrilobular necrosis, 2) distinctive lobular zones of adduct localization with subsequent depletion during the progression of toxicity, 3) drug-protein binding in hepatocytes at subhepatotoxic doses and before depletion of total hepatic glutathione, 4) immunohistochemical evidence of drug binding in the nucleus, and 5) adduct in metabolically active and dividing hepatocytes and in macrophagelike cells in the regenerating liver.

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PubMed1990

Pharmaco-toxicological effects of acetaminophen in rodents. Battery of tests to screen potential analgesic acetaminophen derivatives.

The pharmacological effects of acute oral administration of acetaminophen have been extensively evaluated in rodents. Using this drug as reference compound we have also standardized several pharmaco-toxociological tests in order to select new analgesic-antipyretic acetaminophen derivatives. According to the results obtained in this work, the following battery of assays is proposed to screen these compounds: a) pharmacological: antipyretic activity against Brewer's yeast-induced pyresis in rats; analgesic activity against chemical-induced writhings in mice and paw pressure test in rats; b) toxicological: oral acute toxicity in mice with and without phenobarbital pretreatment; determination of SGOT and SGPT activities as well as total bilirubin in mice. The usefulness of this procedure in the evaluation of drug effects is also considered.

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PubMed1988

Inhibition by ranitidine of acetaminophen conjugation and its possible role in ranitidine potentiation of acetaminophen-induced hepatotoxicity.

Pretreatment with ranitidine (RA) potentiates the hepatotoxicity of acetaminophen (APAP) in male Fischer 344 rats. The present studies were undertaken to investigate the role of APAP metabolism in this potentiation. Administration of RA (50 mg/kg p.o.) to male Fischer 344 rats 30 min before [3H]APAP (750 mg/kg p.o.) increased the plasma concentrations of acetaminophen at 2 hr (193%) and 4 hr (277%) after APAP. Covalent binding of [3H]APAP-related material to hepatic macromolecules in RA-pretreated animals was similar to APAP alone values up to 12 hr after treatment; however, 24 hr after APAP, binding in the RA-pretreated animals was twice that observed in animals given [3H]APAP alone. Urinary excretion (0-24 hr) of APAP and APAP glucuronide were reduced in ranitidine-pretreated animals to 64 and 66% of control, respectively, indicating that in vivo RA altered APAP conjugation with glucuronic acid. APAP uridine diphosphoglucuronyltransferase activity in rat hepatic microsomes was competitively inhibited by RA (0.1-2 mM). The Ki apparent for RA inhibition of APAP uridine diphosphoglucuronyltransferase was 0.04 mM. In contrast, neither APAP nor 4-nitrophenol sulfotransferase activity in rat hepatic cytosol was inhibited by RA at concentrations up to 5 mM. Together, these results support the suggestion that RA-mediated alterations of APAP conjugation may explain the potentiation of APAP-induced hepatotoxicity by RA in rats.

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PubMed1996

Protection by clofibrate against acetaminophen hepatotoxicity in male CD-1 mice is associated with an early increase in biliary concentration of acetaminophen-glutathione adducts.

Repeated treatment with clofibrate (CFB) significantly increased hepatic glutathione (GSH) content and also diminished acetaminophen's (APAP) selective protein arylation, GSH depletion, and severity of hepatocellular necrosis. The present work was conducted to evaluate the role of elevated GSH and APAP detoxifying pathways in the amelioration of APAP's toxicity by CFB. Male CD-1 mice received 500 mg CFB/kg, i.p., daily for 10 days. Controls were given corn oil vehicle. They were challenged with 700 mg APAP/kg in 50% propylene glycol/water after an overnight fast. Results indicate that CFB pretreatment had no effect on 24-hr urinary excretion of APAP-glucuronide, sulfate, or GSH-derived conjugates; however, there was 50% less unchanged APAP excreted in urine of CFB-pretreated mice. CFB also did not alter microsomal UDP-glucuronyl transferase activity toward APAP in vitro. However, elimination of APAP from plasma and liver was much greater in CFB-pretreated mice. This was accompanied by elevated biliary APAP-GSH content in CFB-pretreated mice at 2 hr after APAP dosing with diminished levels in bile at 12 hr. The CFB-induced increase in biliary excretion of APAP-GSH may mediate the protection against APAP-induced hepatotoxicity.

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PubMed1988

Immunochemical analysis of acetaminophen covalent binding to proteins. Partial characterization of the major acetaminophen-binding liver proteins.

A sensitive immunoassay for detecting acetaminophen (APAP) bound to proteins was developed using an affinity purified antibody directed against the N-acetylated end of the APAP molecule. Western blots of electrophoretically resolved liver proteins taken from mice given an hepatotoxic dose of APAP demonstrated that nearly 85% of the total detectable protein-bound APAP was covalently associated with proteins of 44 and 58 kD. Pretreatment of liver extracts with the sulfhydryl-specific reagent, N-ethylmaleimide (NEM), prior to derivatization with the reactive metabolite of APAP, N-acetyl-p-benzoquinone imine (NAPQI), greatly reduced immunochemically detectable APAP-protein adducts and indicated that the antibody detects protein-thiol conjugates of APAP. To investigate the basis of the binding selectivity in vivo, a variety of systems which yielded APAP-protein adducts were analyzed. Systems which activate APAP enzymatically, as in hepatocyte suspensions or in post-mitochondrial (S9) fractions fortified with an NADPH-regenerating system, resulted in a protein binding profile similar to that produced in vivo. Conversely, when extracts or cells were treated with chemically synthesized NAPQI, an alternative protein binding profile was obtained. Two-dimensional electrophoretic analysis of the reduced protein thiol (PSH) content of liver proteins using [3H]NEM labeling revealed that the 58 kD APAP-binding proteins were rich in PSH, whereas the major 44 kD binding protein had virtually no detectable PSH. Many PSH-rich proteins that were not arylated in vivo did bind NAPQI in vitro. However, the 44 kD proteins were not arylated when chemically synthesized NAPQI was added to homogenates or cell suspensions. The present data further suggest that, in addition to the amount and reactivity of free protein sulfhydryls, the cellular localization with respect to the cytochrome P-450 activation site may influence the susceptibility of proteins to NAPQI binding. These findings signal the need for caution in interpreting studies of APAP mechanisms that rely solely on NAPQI addition.

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PubMed1988

Identification of S-(2,5-dihydroxyphenyl)-cysteine and S-(2,5-dihydroxyphenyl)-N-acetyl-cysteine as urinary metabolites of acetaminophen in the mouse. Evidence for p-benzoquinone as a reactive intermediate in acetaminophen metabolism.

S-(2,5-Dihydroxyphenyl)-cysteine and S-(2,5-dihydroxyphenyl)-N-acetyl-cysteine [the cysteine- and N-acetyl-cysteine adducts, respectively, of hydroquinone (HQ)] were identified and quantified in the urine of mice administered [ring-U-14C]acetaminophen [14C]APAP, 200 mg kg-1, i.p.). Urine was collected for 24 h and fractionated by HPLC to isolate the above adducts. These conjugates were then converted to a common derivative, viz. O,O',S-tris-acetyl-3-thio-hydroquinone, which was characterized by GC/MS. Neither of the HQ adducts was detected in the urine of control mice which had not received APAP. Quantification of urinary HQ-cysteine and HQ-N-acetyl-cysteine was performed by HPLC techniques, which indicated that these conjugates accounted for approx. 1.5% of the administered dose of APAP after 24 h, a figure which is equivalent to 6.3% of the corresponding APAP-thiol conjugates in the urine. These findings provide strong indirect evidence that p-benzoquinone is formed as a reactive, but apparently non-hepatotoxic, metabolite of APAP in vivo.

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PubMed1983

Acetaminophen nephrotoxicity in the rat. II. Strain differences in nephrotoxicity and metabolism of p-aminophenol, a metabolite of acetaminophen.

Acetaminophen (APAP) produces renal necrosis restricted to the straight segment of the proximal tubule in Fischer 344 (F344) rats. On the other hand, Sprague-Dawley (SD) rats are extremely resistant to the nephrotoxic effects of APAP. Such strain differences may be due to different susceptibilities to the nephrotoxic metabolite, p-aminophenol (PAP). PAP administration in both strains of rats resulted in a renal lesion indistinguishable from the APAP-induced renal lesion in F344 rats. The PAP-induced renal lesions in F344 rats, however, were generally more severe than those in SD rats. PAP-induced renal functional changes (elevation in blood urea nitrogen and reduction in the accumulation of p-aminohippurate by renal cortical slices) correlated with strain-dependent histopathological changes. Analysis of urinary metabolites over a 24-hr period following PAP administration (200 and 400 mg/kg) indicated that more PAP was excreted as APAP in SD than in F344 rats. Covalent binding of PAP to renal microsomes in vitro was much greater in F344 rats than in SD rats at substrate concentrations less than 5 mM. These results suggest that strain differences in PAP-induced nephrotoxicity may be related to differences in the intrarenal activation of PAP. Furthermore, strain differences in APAP-induced nephrotoxicity may be related to strain differences in the activation of the nephrotoxic metabolite, PAP.

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PubMed1985

The role of p-aminophenol in acetaminophen-induced nephrotoxicity: effect of bis(p-nitrophenyl) phosphate on acetaminophen and p-aminophenol nephrotoxicity and metabolism in Fischer 344 rats.

Acetaminophen (APAP) produces proximal tubular necrosis in Fischer 344 (F344) rats. Recently, p-aminophenol (PAP), a known potent nephrotoxicant, was identified as a metabolite of APAP in F344 rats. The purpose of this study was to determine if PAP formation is a requisite step in APAP-induced nephrotoxicity. Therefore, the effect of bis(p-nitrophenyl) phosphate (BNPP), an acylamidase inhibitor, on APAP and PAP nephrotoxicity and metabolism was determined. BNPP (1 to 8 mM) reduced APAP deacetylation and covalent binding in F344 renal cortical homogenates in a concentration-dependent manner. Pretreatment of animals with BNPP prior to APAP or PAP administration resulted in marked reduction of APAP (900 mg/kg) nephrotoxicity but not PAP nephrotoxicity. This result was not due to altered disposition of either APAP or acetylated metabolites in plasma or renal cortical and hepatic tissue. Rather, BNPP pretreatment reduced the fraction of APAP excreted as PAP by 64 and 75% after APAP doses of 750 and 900 mg/kg. BNPP did not alter the excretion of APAP or any of its non-deacetylated metabolites nor did BNPP alter excretion of PAP or its metabolites after PAP doses of 150 and 300 mg/kg. Therefore, the BNPP-induced reduction in APAP-induced nephrotoxicity appears to be due to inhibition of APAP deacetylation. It is concluded that PAP formation, in vivo, accounts, at least in part, for APAP-induced renal tubular necrosis.

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PubMed1997

Effects of fructose-induced hypertriglyceridemia on hepatorenal toxicity of acetaminophen in rats: role of pharmacokinetics and metabolism of acetaminophen.

Fructose-induced hypertriglyceridemic rats become resistant to hepatotoxicity and susceptible to nephrotoxicity of acetaminophen (APAP), as compared with normal ones. The present study was designed to test the hypothesis that alterations in the distribution of APAP and in the intrinsic susceptibility to toxicants are responsible for the alteration in hepatorenal toxicity of APAP in fructose-induced hypertriglyceridemic rats. Following APAP-administration (750 mg/kg, i.p.), fructose-pretreated rats (25% fructose in drinking water for 5 weeks) showed nephrotoxicity of APAP more promptly and more severely than normal ones. Renal APAP-concentrations at the early phase (15 and 30 min. after APAP-administration) were significantly greater in fructose-pretreated rats than those in normal ones. Plasma and hepatic APAP concentrations in fructose-pretreated rats were greater than those in normal ones only at the later phase (plasma; 6 hr, liver; 6 and 12 hr after APAP-administration). There were no significant differences in the APAP-induced depletion of hepatic and renal glutathione and in the basal hepatic and renal cytochrome P-450 contents between these rats. Fructose-pretreated rats were also more susceptible to p-aminophenol (PAP), a nephrotoxic metabolite of APAP, than normal rats. Therefore, enhanced susceptibility to APAP-nephrotoxicity in fructose-pretreated rats may be due, at least in part, to increased renal APAP concentration and increased intrinsic susceptibility to the metabolic nephrotoxicant.

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PubMed1997

Effects of fructose-induced hypertriglyceridemia on hepatorenal toxicity of acetaminophen in rats. II. Role of enhancement of fructose metabolism and overproduction of triglyceride in the liver and kidney on hepatorenal toxicity of acetaminophen.

Fructose-induced hypertriglyceridemic rats are resistant to hepatoxicity and susceptible to nephrotoxicity of acetaminophen (APAP) as compared with normal ones. The present studied were designed to evaluate how fructose-treatment affects the developmental mode of hepatorenal toxicity of APAP. First, following fructose-pretreatment for various durations (1 day, 1 week or 3 weeks), 1-day-fructose-pretreatment induced hypertriglyceridemia and enhancement of APAP-nephrectoxicity simultaneously. However, it took at least 3 weeks for fructose-pretreatment to reduce APAP-hepatotoxicity. Second, following fructose, sucrose or glucose-pretreatment for 3 weeks, fructose-pretreated rats showed marked hypertriglyceridemia and modification of APAP-hepatorenal toxicity. Sucrose-pretreated rats showed less effects than fructose-pretreated rats. Glucose-pretreated rats showed no changes in plasma triglyceride and APAP-hepatorenal toxicity. Third, rats with hypertriglyceridemia induced by olive oil or Triton WR-1339 which did not produce enhanced metabolism and triglyceride-overproduction in the liver and kidney showed no modification of APAP-hepatorenal toxicity. Pretreatment of glycerol which was metabolized in liver and kidney and induced an overproduction of triglyceride resulted in an enhancement of APAP-nephrotoxicity. These results indicate that an enhancement of fructose metabolism and an overproduction of triglyceride in liver and kidney are responsible for the modification of APAP-hepatorenal toxicity in fructose-induced hypertriglyceridemic rats.

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PubMed1997

Enhanced nephrotoxicity of acetaminophen in fructose-induced hypertriglyceridemic rats: contribution of oxidation and deacetylation of acetaminophen to an enhancement of nephrotoxicity.

Fructose-induced hypertriglyceridemic Sprague-Dawley (SD) rats become resistant to hepatotoxicity and susceptible to nephrotoxicity of acetaminophen (APAP) as compared with normal SD rats. Fischer-344 rats, which are susceptible to APAP nephrotoxicity, have two toxic metabolic pathways involving cytochrome P450-dependent oxidation of APAP to N-acetyl-p-benzoquinone imine (NAPQI) and P450-independent deacetylation of APAP to p-aminophenol (PAP). SD rats, however, have only the former pathway. This study was undertaken to investigate whether alterations in the metabolic pathways of APAP and in the intrinsic susceptibility to toxic metabolites are responsible for an enhancement of APAP nephrotoxicity in the fructose-pretreated SD-rats. In the non-pretreated rats, the inhibition of APAP oxidation by the MFO inhibitor, piperonyl butoxide, and deacetylation by carboxyesterase inhibitor, bis(p-nitrophenyl)phosphate, did not alter APAP-induced renal lesions. In contrast, these inhibitors protected the fructose-pretreated rats from APAP-induced renal lesions. Since there were no differences in the severity of gentamicin-, chloroform, and 45 min-ischemia/reperfusion-induced renal lesions between the non-pretreated and the fructose-pretreated rats, it is unlikely that the increased intrinsic susceptibility to chemicals and their metabolites in the fructose-pretreated rats is a major factor in the enhancement of APAP nephrotoxicity. These results indicate that the enhancement of APAP nephrotoxicity in the fructose-pretreated rats is due, at least in part, to an alteration in metabolic pathways of APAP.

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PubMed2006

Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15. Potential implications in acetaminophen-induced hepatotoxicity.

The importance of uridine 5'-diphosphate-glucuronosyltranferases (UGT) 2B15 and other UGT enzymes (1A1, 1A6, and 1A9) in glucuronidating acetaminophen (APAP) is demonstrated. The kinetics and contributions of various UGTs in glucuronidating APAP are presented using clinically and toxicologically relevant concentrations of the substrate. UGT 1A9 and UGT 2B15 contribute significantly toward glucuronidating APAP when incubations were conducted in either phosphate or Tris-HCl buffers at 0.1 and 1.0 mM substrate concentrations. At 10 mM APAP, UGT 1A9 is a significant enzyme responsible for metabolizing APAP in either one of the buffers. UGT 1A1 is the next most important enzyme in glucuronidating APAP at this high substrate concentration. The contribution of UGT 1A6 at 10 mM APAP concentration became obscured by similar relative activities exhibited by UGTs 1A7, 1A8, and 2B7. These observations may reflect the differences in kinetic parameters for APAP glucuronidation by the individual UGTs. UGT 1A1 demonstrated Hill kinetics while UGT 1A9 displayed Michaelis-Menten kinetics. Substrate inhibition kinetics is observed with UGT 1A6, UGT 2B15, and human liver microsomes. The substrate inhibition is confirmed by employing stable isotope-labeled APAP as the substrate, while APAP glucuronide is used to test for inhibition of d4-APAP glucuronide. The in vitro hepatotoxicity caused by APAP in combination with phenobarbital or phenytoin is demonstrated in this study. The inhibition of APAP glucuronidation by phenobarbital leads to an increase in APAP-mediated toxicity in human hepatocytes. The toxicity to hepatocytes was further increased by coadministering APAP with phenytoin and phenobarbital. This synergistic increase in toxicity is postulated to be due to inhibition of UGTs (1A6, 1A9, and 2B15) responsible for detoxifying APAP through the glucuronidation pathway.

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PubMed1995

Evidence for common binding of acetaminophen and bromobenzene to the 58-kDa acetaminophen-binding protein.

Acetaminophen (APAP) toxicity has been closely associated with covalent binding to a cytosolic protein of approximately 58 kDa (58-ABP). To determine if metabolites of other toxicants might also selectively target this protein, studies were conducted with bromobenzene (BrB). Mice were given phenobarbital (80 mg/kg/d x 4 d) and were killed 4 h after challenge with 800 mg BrB/kg. Liver cytosols from BrB-treated or naive mice were incubated with an APAP activating system. Cytosolic fractions were analyzed for APAP binding by Western blotting with anti-APAP antibody. Binding to 58-ABP was selectively decreased in liver cytosol from BrB-treated mice while binding to other targets was minimally affected. Western blotting of the same samples with anti-58-ABP antisera showed that this decrease in binding did not result from diminished 58-ABP content. HPLC analysis of APAP-N-acetyl cysteine conjugate formation in vitro indicates that APAP activation was not altered in the incubates with cytosol from BrB-treated mice. These results suggest that the 58-ABP may be a common target for electrophiles in reactive intermediate toxicity.

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PubMed2005

Shift from biliary to urinary elimination of acetaminophen-glucuronide in acetaminophen-pretreated rats.

Despite its toxicity, acetaminophen (APAP) is used increasingly as an analgesic, antipyretic, and anti-inflammatory agent. We examined the effect of prior exposure to APAP on its biliary and urinary elimination. The biliary and urinary elimination of a test dose of APAP (150 mg/kg i.v.) was determined in male Wistar rats 24 h after pretreatment with vehicle, a single dose (1.0 g/kg i.p.), or increasing daily doses (0.2, 0.3, 0.6, and 1.0 g/kg/day i.p.) of APAP. Although elimination of the parent APAP was minimally affected, biliary excretion of APAP glucuronide was significantly decreased 70 and 80%, whereas urinary excretion was significantly increased 90 and 100% in the groups pretreated with single and repeated doses of APAP, respectively, relative to vehicle controls. Western analysis and confocal immunofluorescent microscopy indicated a marked increase in hepatic expression of multidrug resistance-associated protein 3 (Mrp3) in both groups pretreated with APAP, relative to expression of Mrp2. ATP-dependent transport of [3H]taurocholate, an Mrp3 substrate, was significantly increased in basolateral liver plasma membrane vesicles from rats pretreated with repeated doses of APAP relative to controls. Enterohepatic recirculation of APAP glucuronide after administration of the same test dose of the drug was significantly decreased in rats pretreated with repeated doses of APAP. These data indicate that APAP pretreatment induced a shift from biliary to urinary elimination of APAP glucuronide, consistent with the increased expression of Mrp3 in the basolateral domain of the hepatocyte. We postulate that decreased enterohepatic recirculation contributes to decreased APAP hepatotoxicity by reducing liver exposure.

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PubMed2000

Acetaminophen controlled-release sprinkles versus acetaminophen immediate-release elixir in febrile children.

Current acetaminophen (APAP) formulations approved for antipyretic use in children require up to five doses/day, which compromise compliance and risk breakthrough fever over 4 hours after dosing. A total of 112 evaluable febrile children received oral APAP-equivalent doses of either one dose of APAP controlled release (CR) as sprinkles on applesauce or one dose q 4 hours x 2 of APAP immediate-release (IR) elixir in an 8-hour, double-blind, double-dummy, randomized, multicenter study. Prior or concurrent antibiotic use did not significantly affect either the magnitude or the pattern of temperature reduction during the 8-hour observation period. Significantly greater aural temperature reductions were found with APAP-CR than with APAP-IR at 4 and 5 hours. However, the 8-hour AUCs of temperature reduction were not significantly different between treatments. Pharmacokinetic/pharmacodynamic modeling of APAP was performed in 8 patients with values in both treatments similar to previous results, except for expected differences in AUC0-infinity. Similar 8-hour temperature reduction for APAP-CR (one dose) and APAP-IR (two doses) demonstrates the efficacy of APAP-CR as an antipyretic in children 2 to 11 years of age. A decrease in the number of APAP daily doses and the prolonged antipyretic effect of APAP-CR may assist those who care for febrile children at home.

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PubMed2001

Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms.

Interindividual variability in acetaminophen (APAP) glucuronidation may contribute to differences in susceptibility to APAP intoxication in humans. The purpose of this study was to identify the relevant UDP-glucuronosyltransferase (UGT) isoforms mediating APAP-UGT activity in human liver microsomes (HLMs). APAP-UGT activities and enzyme kinetics were determined using HLMs from 56 donors and nine recombinant human UGTs. Activities mediated by UGT1A1, UGT1A4, UGT1A9, and UGT2B7, and relative UGT1A6 protein content were quantified using 20 livers. More than 15-fold variation in liver microsomal APAP-UGT activities was observed with a distribution skewed toward lower activities. Although most UGTs could glucuronidate APAP, UGT1A1, UGT1A6, and UGT1A9 were most active. UGT1A6 was a relatively high-affinity (K(m) = 2.2 mM), low-capacity enzyme; UGT1A1 was intermediate in affinity (K(m) = 9.4 mM) and capacity; and UGT1A9 was a low-affinity (K(m) = 21 mM), high-capacity enzyme. K(m) values were similar to UGT1A1 in high- and intermediate-activity HLMs (6-10 mM) and UGT1A9 in low-activity HLMs (10-55 mM). APAP-UGT activities correlated best with propofol-UGT (r = 0.85; UGT1A9) and bilirubin-UGT (r = 0.66; UGT1A1) activities, but poorly with UGT1A6 protein (r = 0.30). A kinetic model was constructed from these data that identified UGT1A9 as the predominant APAP-UGT (>55% total activity) in HLMs over a clinically relevant APAP concentration range (50 microM-5 mM). UGT1A1 was also predicted to contribute substantially at toxic concentrations (>1 mM; >28% activity), whereas UGT1A6 was most active at relatively low concentrations (<50 microM; >29% activity).

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