Potential Pharmacokinetic Drug-Drug Interactions between Cannabinoids and Drugs Used for Chronic Pain.

Choosing an appropriate treatment for chronic pain remains problematic, and despite the available medication for its treatment, still, many patients complain about pain and appeal to the use of cannabis derivatives for pain control. However, few data have been provided to clinicians about the pharmacokinetic drug-drug interactions of cannabinoids with other concomitant administered medications. Therefore, the aim of this brief review is to assess the interactions between cannabinoids and pain medication through drug transporters (ATP-binding cassette superfamily members) and/or metabolizing enzymes (cytochromes P450 and glucuronyl transferases).

Acetaminophen-Induced Liver Damage in Hepatic Steatosis.

One of the most used painkillers is acetaminophen (APAP), which is safe at the right dose. However, several studies have described populations susceptible to APAP-induced liver damage, mainly in livers with steatosis. Thus, clinicians should consider the presence of obesity and other chronic liver diseases like nonalcoholic fatty liver disease (NAFLD) when indicating treatment with APAP. Liver damage from this drug is generated through its metabolite N-acetyl-p-benzoquinone imine, which is detoxified with glutathione (GSH). Prior depletion of GSH in steatotic hepatocytes plays a key role in APAP-induced hepatotoxicity in people with obesity and NAFLD. The knowledge about the damage to the liver or APAP in susceptible people like the obese and those with NAFLD is of great relevance for the sanitary sector because it would imply strategies of different therapeutic approach in such patients. This paper reviews the role of APAP in liver damage in the presence of obesity, NAFLD, and nonalcoholic steatohepatitis.

Validated analytical study of the effect of Lycopene on the pharmacokinetics of Paracetamol and Chlorzoxazone in rats

Lycopene was reported to influence some cytochrome P450 enzymes activity. The present study investigates the effect of lycopene on the pharmacokinetics of paracetamol and chlorzoxazone. Lycopene (20 mg/kg) was intra-peritoneally administered to two groups of rats for eight consecutive days and two other groups were given vehicle. On the eighth day, chlorzoxazone and paracetamol were separately intravenously administered to a lycopene group and a control group. Blood samples were collected at different time intervals, treated and analyzed using HPLC. The HPLC method used for paracetamol analysis was based on isocratic elution using a mobile phase consisting of water: methanol, (77:23 v/v) at a flow rate 1 mL min−1, Kromasil C18 column, and UV detection at 254 nm using caffeine as internal standard. About chlorzoxazone, separation was carried out using water: acetonitrile (60: 40, v/v) as the mobile phase at a flow rate 1 mL min−1, Inertsil ODS-3 C18 column, UV detection at 283 nm and esomeprazole as internal standard. Statistical analysis of the pharmacokinetic data using student t test showed a significant increase in AUC 0-t , AUC 0-Inf and t1/2 of paracetamol (P<0.05) and of chlorzoxazone (P<0.05) in the groups pretreated with lycopene (20 mg/kg), significant increase in the volume of distribution of paracetamol (P < 0.05), but no significant difference in that of chlorzoxazone. In other words, paracetamol and chlorzoxazone showed significant decrease (P < 0.05), respectively. These results demonstrate that treatment of rats with Lycopene (20mg/kg, ip) has a significant effect on the metabolic clearance and the pharmacokinetics of both drugs

Bioequivalence and Pharmacokinetic Evaluation Study of Acetaminophen vs. Acetaminophen Plus Caffeine Tablets in Healthy Mexican Volunteers.

OBJECTIVE: The aim of this clinical trial was to establish the bioequivalence of two tablets containing acetaminophen 650 mg (reference) and acetaminophen 650 mg plus caffeine 65 mg (test), administered orally, in fasting conditions in healthy Mexican volunteers. METHODS: Blood samples were taken from 21 male and five female individuals, during a 24-h period, to characterize the pharmacokinetic profile of acetaminophen. Plasma samples were quantified by ultra-performance liquid chromatography, tandem mass spectrometry. Pharmacokinetic metrics (maximum plasma concentration, area under the curve from time zero to the last sampling time, and area under the curve from time zero to infinity) were used to determine the 90 % confidence interval of the test/reference coefficient. RESULTS: The geometric mean values for maximum plasma concentration obtained for the reference and test products were 9.46 ± 34.21 and 9.72 ± 32.38 µg/mL, respectively, whereas for the area under the curve from time zero to the last sampling time the values obtained were 34.93 ± 32.58 and 35.89 ± 31.03 µg h/mL for the reference and test formulations, respectively. The 90 % confidence intervals were within the acceptance range (80-125 %). CONCLUSIONS: The test product was bioequivalent to the reference product. A faster absorption was seen in the test formulation in the Mexican population.

Evaluation of peripheral blood microsampling techniques in combination with liquid chromatography-high resolution mass spectrometry for the determination of drug pharmacokinetics in clinical studies.

New bioanalytical assays were developed, validated, and applied in a clinical study for quantitative measurement of acetaminophen concentrations in blood and plasma samples. Furthermore, after validation, the bioanalytical assays were used for determination of pharmacokinetics within a group of six healthy male human volunteers after admission of a single oral dose of 500 mg of acetaminophen. Quantitative analyses were done by means of liquid chromatography-high resolution mass spectrometry and blood samples were collected at various sampling time points using different peripheral blood microsampling techniques. Post-dose peripheral collected blood samples were applied for the preparation of dry blood spots, dried matrix on paper discs, and peripheral plasma. Pharmacokinetic parameters determined were clearance (Cl), area under the curve (AUC), volume of distribution (Vd ), peak concentration (Cmax ), time of occurrence of peak concentration (Tmax ) and half-life time (T½ ). Observed pharmacokinetic values were not statistically (ANOVA) different compared to in literature reported values based on venous blood collection. The present pilot study demonstrated the feasibility of peripheral blood microsampling techniques in combination with quantitative liquid chromatography-high resolution mass spectrometry analysis for the determination of pharmacokinetics in clinical studies.

Equivalência farmacêutica e estudo comparativo dos perfis de dissolução de medicamentos genéricos contendo paracetamol / Pharmaceutical equivalence and comparative study of dissolution profiles of generic drugs containing acetaminophen

Este trabalho teve como objetivo principal comparar, através do estudo de equivalência farmacêutica e do perfil de dissolução in vitro, oito medicamentos genéricos contendo paracetamol 750 mg, comercializados na região central do Rio Grande do Sul. As análises foram realizadas em conformidade com a monografia do paracetamol comprimidos, descrita na Farmacopeia Brasileira (2010). Os genéricos A, B, D, E, F, G e H são equivalentes farmacêuticos do medicamento referência, pois foram aprovados em todos os testes a que foram submetidos. O Genérico C, no entanto, foi reprovado no doseamento. Quando avaliados em relação ao perfil de dissolução, pelos critérios descritos na RDC 31/2010, somente o genérico E não possui o mesmo perfil de dissolução que o medicamento referência, porém quando comparados pela eficiência de dissolução (ED) podemos verificar que somente os Genéricos G, H, F e A possuem a mesma ED que o medicamento referência.

The aim of this study was to compare, by testing their pharmaceutical equivalence and dissolution profiles in vitro, eight generic medicines containing 750 mg paracetamol, marketed in the central region of Rio Grande do Sul (Brazil). Analyses were carried out in accordance with the monograph on paracetamol tablets in the Brazilian Pharmacopoeia (2010). The generic medicines A, B, D, E, F, G and H are pharmaceutically equivalent to the drug reference, since they passed all the tests they underwent. Of all the samples analyzed, only drug E did not have the same dissolution profile as the reference drug, a fact that may interfere with the interchangeability of these products, which is required of a drug being marketed as a generic. Regarding dissolution efficiency (DE), the ANOVA showed a significant difference between the products, so the Tukey test was applied, showing that only the generics A, F, G and H have the same DE as the reference drug.

Effect of repeated administration with subtoxic doses of acetaminophen to rats on enterohepatic recirculation of a subsequent toxic dose.

Development of resistance to toxic effects of acetaminophen (APAP) was reported in rodents and humans, though the mechanism is only partially understood. We examined in rats the effect of administration with subtoxic daily doses (0.2, 0.3, and 0.6g/kg, i.p.) of APAP on enterohepatic recirculation and liver toxicity of a subsequent i.p. toxic dose of 1g/kg, given 24h after APAP pre-treatment. APAP and its major metabolite APAP-glucuronide (APAP-Glu) were determined in bile, urine, serum and liver homogenate. APAP pre-treatment was not toxic, as determined by serum markers of liver damage and neither induced oxidative stress as demonstrated by assessment of ROS generation in liver or glutathione species in liver and bile. APAP pre-treatment induced a partial shift from biliary to urinary elimination of APAP-Glu after administration with the toxic dose, and decreased hepatic content and increased serum content of this conjugate, consistent with a marked up-regulation of its basolateral transporter Mrp3 relative to apical Mrp2. Preferential secretion of APAP-glu into blood decreased enterohepatic recirculation of APAP, thus attenuating liver exposition to the intact drug, as demonstrated 6h after administration with the toxic dose. The beneficial effect of interfering the enterohepatic recirculation was alternatively tested in animals receiving activated charcoal by gavage to adsorb APAP of biliary origin. The data indicated decreased liver APAP content and glutathione consumption. We conclude that selective up-regulation of Mrp3 expression by APAP pre-treatment may contribute to development of resistance to APAP hepatotoxicity, at least in part by decreasing its enterohepatic recirculation.

Bioavailability of two oral-tablet and two oral-suspension formulations of naproxen sodium/paracetamol (acetaminophen): single-dose, randomized, open-label, two-period crossover comparisons in healthy Mexican adult subjects.

BACKGROUND: Naproxen sodium/paracetamol (acetaminophen) is a combination for the treatment of symptomatic pain and fever marketed both as a prescription and an over-the-counter product in Mexico. OBJECTIVE: The aim of these 2 studies was to compare the bioavailability and to determine the bioequivalence of 2 test formulations (an oral-tablet formulation containing the combination of naproxen sodium/paracetamol 275/300 mg and an oral-suspension formulation containing the combination of naproxen sodium/paracetamol 375/300 mg per 15 mL) with their corresponding listed reference-drug formulations in Mexico (a list issued by Mexican health authorities). METHODS: Two separate, single-dose, randomized, open-label, 2-period crossover, postmarketing studies were conducted. For each study, a different set of eligible subjects was selected comprising healthy Mexican adults of either sex, and subjects were randomly assigned to receive 1 test formulation of the combination of naproxen sodium/paracetamol followed by the corresponding reference-drug formulation, or vice versa, with a 1-week washout period between doses. After a 12-hour overnight fast, subjects received a single dose of naproxen sodium/paracetamol 275/300-mg tablet or naproxen sodium/paracetamol 375/300 mg per 15 mL suspension, depending on the study. For the analysis of pharmacokinetic parameters, including C(max), AUC from time 0 (baseline) to 48 hours (AUC(0-48)), and AUC from baseline to infinity (AUC(0-infinity)), blood samples were drawn at baseline and at 0.16, 0.33, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours after administration. The formulations were considered bioequivalent if the geometric mean ratios (test/reference) of the C(max) and AUC were within the predetermined range of 80% to 125%. Tolerability was determined by clinical assessment, monitoring vital signs, laboratory analysis results, and subject interviews regarding adverse events. RESULTS: A total of 26 subjects (15 men, 11 women; mean [SD] age, 29 [8] years [range, 20-50 years]; weight, 63.1 [9] kg [range, 51.4-84.4 kg]; height, 164 [9] cm [range, 149-179 cm]; and body mass index [BMI], 23.53 [2.18] kg/m(2) [range, 18.54-26.82 kg/m(2)]) were enrolled to receive the suspension-dosage formulation; 13 subjects received the suspension-test formulation first. A total of 26 subjects (13 men, 13 women; mean [SD] age, 29 [8] years [range, 18-43 years]; weight, 64.3 [7.7] kg [range, 50.6-80.7 kg]; height, 165 [9] cm [range, 151-181 cm]; and BMI, 23.64 [2.43] kg/m(2) [range, 18.02-26.42 kg/m(2)]) were enrolled to receive the tablet-dosage formulation; 13 subjects received the tablet-test formulation first. No significant period or sequence effects were detected based on analysis of variance. For the suspension-dosage formulation, the 90% CIs for naproxen C(max), AUC(0-48), and AUC(0-infinity) were 93.06% to 104.00%, 93.50% to 98.44%, and 92.14% to 98.99%, respectively, and were 90.09% to 105.90%, 88.58% to 99.34%, and 91.43% to 101.55%, respectively, for paracetamol. For the tablet-dosage formulation, the 90% CIs for naproxen C(max), AUC(0-48), and AUC(0-infinity) were 102.83% to 117.15%, 96.59% to 104.26%, and 96.01% to 102.90%, respectively, and were 94.04% to 121.09%, 95.48% to 105.64%, and 96.64% to 105.42%, respectively, for paracetamol. CONCLUSIONS: In these 2 small studies in healthy Mexican adult subjects, a single dose of naproxen sodium/paracetamol 275/300 mg of the test formulation of the tablet-dosage formulation or a single dose of naproxen sodium/paracetamol 375/300 mg per 15 mL of the test formulation of the suspension-dosage formulation was found to be bioequivalent to the corresponding reference formulations according to the regulatory definition of bioequivalence based on the rate and extent of absorption. All formulations were generally well tolerated.

Relative bioavailability of new formulation of paracetamol effervescent powder containing sodium bicarbonate versus paracetamol tablets: a comparative pharmacokinetic study in fed subjects.

OBJECTIVE: the aim of this relative bioavailability study was to determine the rate and extent of absorption of Alikal Dolor (effervescent powder containing paracetamol 500 mg/sodium bicarbonate 2318 mg)--test formulation (T) in relation to Parageniol (paracetamol 500 mg coated tablets)--reference formulation (R). METHODS: 18 healthy volunteers (10 male and 8 female aged between 21 and 46 years) received, after 2 h of standardized breakfast, a single oral dose with 220 ml of water, in an open, randomized, crossover study, with a 7-day wash-out period. Paracetamol concentrations were established at 0, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, 90 min and at 2, 4, 6, 8 and 10 h postdose by HPLC with an ultraviolet detector. RESULTS: the regression coefficient determined for paracetamol calibration curves was 0.9983 +/- 0.0034 and the working range was from 0.2 to 50 microg/ml. The quantification limit was 0.2 microg/ml. The rate of absorption was significantly greater (p < 0.03) for T (T(max) = 20.4 min) compared with R (T(max) = 38.4 min). Extent of absorption over the first 30 min postdose AUC((0-30 min)) was 4.21-fold greater (p < 0.03) for T compared with R, without differences between C(max.) The 90% CI on the geometric mean for C(max), AUC((0-10 h)) and AUC((0-)) ratios (T/R) were within the limits of 0.80-1.25, indicating both formulations were bioequivalent with respect to these parameters. CONCLUSION: paracetamol was absorbed at least twice as fast from T-containing sodium bicarbonate compared with R. This pharmacokinetic feature could prove crucial from the therapeutic point of view as it would allow a lower latency in the action time of paracetamol in producing its analgesic and antithermal effect.

A pharmacokinetic study investigating the rate of absorption of a 500 mg dose of a rapidly absorbed paracetamol tablet and a standard paracetamol tablet.

OBJECTIVE: A rapidly absorbed tablet formulation of paracetamol containing sodium bicarbonate (PS) has been previously shown to be absorbed at least twice as fast as a standard paracetamol tablet (P) at a 1 g dose. In South America and Asia it is customary for patients to take a 500 mg dose of analgesic. The objective of this pharmacokinetic study was to compare the rate of absorption of PS versus P at a 500 mg dose. RESEARCH DESIGN AND METHODS: An open, randomized, single dose, cross-over study. Thirty Hispanic healthy volunteers randomly received a 500 mg dose taken orally with 50 mL of water 2 h after a standard breakfast. Blood samples were taken up to 10 h post-dose. Plasma concentrations of paracetamol were determined by HPLC with UV detection. MAIN OUTCOME MEASURES: AUC(0-30 min), C(plasma 30 min) and T(max) were analyzed non-parametrically by the Wilcoxon's rank sum test. A linear mixed effects model was used to analyze the logarithmically transformed AUC(0-alpha) and C(max). Bioequivalence was accepted if the 90% confidence intervals (CI) for the ratio of the means of the primary pharmacokinetic variable AUC(0-alpha) lay completely within the range 0.80-1.25. RESULTS: AUC(0-30 min) and C(plasma 30 min) were significantly greater and T(max) was significantly shorter (all p < 0.0001) for PS versus P. The formulations were bioequivalent for AUC(0-alpha) (90% CI 0.99:1.05) and no statistical difference was seen for C(max) (95% CI 0.91:1.14). CONCLUSIONS: Paracetamol was absorbed at least twice as fast from PS compared to P at a 500 mg dose. The extent of absorption was equivalent for both formulations.

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.

Evaluation of acetaminophen P-glycoprotein-mediated salivary secretion by rat submandibular glands.

The constant ratio between saliva and plasma acetaminophen concentrations (S/P) during the elimination phase is assumed to result from the equilibrium established among the free-drug concentrations in the arterial blood, venous blood and saliva. Salivary secretion of acetaminophen is assumed to result from a passive diffusion of the drug to saliva from the blood that supplies the salivary glands. However, the constant S/P ratio during acetaminophen disposition and the finding that P-glycoprotein (P-gp), a protein recognized to pump substrates out of the cell, is expressed in duct cells of the submandibular glands questions the mechanisms involved in acetaminophen salivary secretion. Thus, we intended to evaluate the existence of a P-glycoprotein-mediated transport of acetaminophen in rat submandibular glands. Acetaminophen (30 mg/kg, i.v.) pharmacokinetics was assessed in controls and in rats pre-treated with erythromycin (100 mg/kg) as a P-glycoprotein inhibitor. Acetaminophen pharmacokinetic parameters were calculated from saliva and plasma levels considering a non-compartmental analysis. Mean plasma and salivary profiles of control and pre-treated animals were almost superimposable. No difference could be found in S/P ratios in control and erythromycin pre-treated animals (P > 0.05). Moreover, no statistical difference could be found in the kinetic parameters calculated from saliva or plasma drug level (P > 0.05). These observations indicate that acetaminophen salivary secretion in rat submandibular glands is not related to P-glycoprotein-mediated transport under the experimental conditions of the present work.

Analgésicos no opioides en dolor postoperatorio pediátrico / Analgesic not opioids in pediatric postoperative pain

El dolor postoperatorio es todavía subvalorado en la población pediátrica. Por otro lado, entre las publicaciones que abordan el tema del dolor postoperatorio solo un 10 por ciento de ellas incluye a la población menor de 15 años. Las alternativas terapéuticas en base a analgésicos no opiaceos es restringida en niños, ya que sólo un 20 por ciento del total de las drogas disponibles en el mercado ha probado su eficacia y seguridad en esta población. un analgésico antiguo es el acetaminofeno, acumulando la mayor cantidad de estudios. Los antinflamatorios no esteriodales (AINEs) han ganado popularidad en el manejo del dolor postoperatorio pediátrico. El objetivo de esta revision es determinar cuáles son las indicaciones y las dosis mas racionales y seguras para el tratamiento del dolor agudo en niños.

Postoperatory pain is still subvaluated in pediatric population. On the other hand, only 10 percent of publications discussing postoperatory pain subjects includes a population under age 15. Therapeutic alternatives based on nonopiate analgesics are restrained for children as only 20 percent of the total available drugs in the market has proven their efficacy and safety in children. An old analgesic is acetaminophen, which accumulates most part of studies. Nonsteroidal antinflammarory drugs (NSAI) are gaining popularity to manage postoperatory pain in children. The objective of this revision is to determine the most rational and safest indications and dosages when treating acute pain in children.

Is acetaminophen, and its combination with pamabrom, an effective therapeutic option in primary dysmenorrhoea?

Primary dysmenorrhoea is the most frequent gynaecological condition, with a prevalence of 40 - 90% in women within the reproductive age. It is characterised by cyclic pelvic pain related to menstrual period, vomiting and headache. As prostaglandins and leukotrienes appear to be a major causative factor in this condition, NSAIDs are the first choice for treatment. Acetaminophen is an over-the-counter analgesic/antipyretic agent widely used in primary dysmenorrhoea as monotherapy or in combination. It has a weak inhibitory action on peripheral prostaglandin synthesis. Acetaminophen displays good gastrointestinal tolerance without any effect on haemostasis. Its combination with pamabrom, a mild diuretic agent, (Women s Tylenol Menstrual Relief Caplets, Midol Teen) was approved by the FDA for use in this indication. Nevertheless, the available information concerning the efficacy of acetaminophen in primary dysmenorrhoea is limited and not conclusive with respect to other NSAIDs or even placebo. The clinical evidence regarding the association with pamabrom is even more scarce. Well-designed, randomised, controlled trials are required to demonstrate the efficacy of the combination of acetaminophen plus pamabrom in the treatment of primary dysmenorrhoea.

Importance of entero-salivary recirculation in paracetamol pharmacokinetics.

The contribution of an entero-salivary recirculation (salivary secretion-swallowed-reabsorption of drug from the gastrointestinal tract) to the values of the pharmacokinetic parameters of paracetamol was studied in a two-way crossover design. Five healthy volunteers took a tablet of Paracetamol (500 mg) in two occasions separated by a washout period. The difference between the two treatments consisted of saliva that was allowed or not to be swallowed during the 4 h of study. No statistically significant differences were found in the values of the pharmacokinetic parameters between treatments. The half-life time calculated from salivary levels was similar to the values previously reported by other authors. The percent of the oral dose excreted in saliva during 4 h of study was very low (0.1%). Secondary peaks appeared in 8 of 10 profiles. The lack of influence of salivary secretion on the pharmacokinetic parameters of Paracetamol and the low percent secreted in this fluid suggests that entero-salivary recirculation is a possible physiological phenomenon undergoing after oral administration, but it is not one of the principal phenomenon that defines the pharmacokinetic of the drug. We confirm that working with salivary samples in pharmacokinetic studies of paracetamol is a useful tool.

Bioequivalence study of paracetamol tablets: in vitro-in vivo correlation.

The bioequivalence of three chemically equivalent paracetamol generic Mexican products (500 mg tablets) was evaluated in 12 healthy volunteers using the American innovator product (Tylenol, McNeil, Fort Washington, PA), as the reference. Single oral doses of each product were administered at 1-week intervals using a 4 x 4 Latin square design balanced for the first residual effect. The total amount of paracetamol excreted in urine in 24 hr was taken as a measure of bioavailability. In addition, moment analysis was used to estimate in vitro mean dissolution time (MDT) from dissolution profiles obtained following the USP 23 dissolution test specified for paracetamol tablets and to estimate in vivo mean residence time (MRT) from urinary excretion data. Significant differences in the dissolution performance and in the cumulative amount of paracetamol excreted in urine up to 24 hr were observed when the data were analyzed by analysis of variance (ANOVA) (p < .05). Classical and Westlake 90% confidence limits, as well as the two-sided t test proposed by Schuirmann, and the Anderson-Hauck power analysis supported the final conclusion that only one of the three generic paracetamol products studied can be considered equivalent to the reference product Tylenol. A linear correlation between in vitro MDT and in vivo MRT was found.

Predicting concentrations in children presenting with acetaminophen overdose.

OBJECTIVE: To predict serum concentrations to evaluate and improve guidelines for the treatment of children (1 to 5 years) with accidental ingestion of acetaminophen elixir. METHODS: Acetaminophen concentrations for 1000 children were simulated with pharmacokinetic parameters and their expected variability. The distribution of concentrations arising from a 300 mg/kg dose at different age groups was predicted. These predictions were validated by comparison with concentrations obtained at 4 hours from 121 children with accidental ingestion of acetaminophen elixir. RESULTS: No child who presented with overdose had a concentration in the probable risk area of the Rumack-Matthew toxicity nomogram. Enteral charcoal administered 98 minutes (SD 44) after ingestion had no effect on serum concentrations. The simulation predicted that an acetaminophen dose of 300 mg/kg would result in concentrations of 32 to 208 mg/L (95% CI) at 4 hours after ingestion. The maximum concentration occurred before 2 hours in 95% of simulated children. CONCLUSION: Children (1 to 5 years) with reported ingestion of >250 mg/kg acetaminophen elixir should have serum concentrations measured at 2 hours after ingestion rather than at the 4-hour time point recommended in adults. This can be expected to speed discharge and reduce anxiety. The use of enteral charcoal is unlikely to enhance acetaminophen elimination, unless it is given within an hour of acetaminophen ingestion.