Plasma Acetaminophen Concentrations Research Articles

Pharmacokinetics of multiple oral doses of acetaminophen in equine neonates.

To determine the pharmacokinetics and clinical safety of acetaminophen after oral administration of 40 mg/kg q 12 hours or 60 mg/kg q 24 hours for 14 days. 12 healthy light-breed neonatal foals. 6 foals received acetaminophen at 40 mg/kg q 12 hours and 6 foals received 60 mg/kg q 24 hours for 14 days. The study dates were January 31 to April 15, 2023. Physical examinations were performed daily. Plasma disposition of acetaminophen was determined after the first, mid-point drug administration. Hematology and biochemistry analysis was performed before the study, day 7, and the last day of drug administration. Plasma acetaminophen concentrations were determined by high-performance liquid chromatography. Plasma pharmacokinetic parameters were estimated using noncompartmental analysis. No statistically significant changes occurred on hematology or biochemistry profiles. Elevations in γ-glutamyl transferase (GGT) and sorbitol dehydrogenase (SDH) were noted in 4 foals at various time points. The maximum plasma concentration (Cmax) occurred within 2 hours for both doses. The 60 mg/kg dose resulted in a larger median Cmax (range) at 28 μg/mL (22-32) than the 40 mg/kg dose at 23 μg/mL (19-27). The median area under the concentration-vs-time curve from 0 to 8 hours (AUC0-8 hour [range]) was 100 h•µg/mL (82-100) at 40 mg/kg and 128 h•µg/mL (120-168) for 60 mg/kg. Trough concentrations decreased over time for both regimens. Foals tolerate oral acetaminophen at 40 mg/kg q 12 hours or 60 mg/kg q 24 hours. Further analgesic and antipyretic studies will help to delineate optimal dosage regimens of acetaminophen to treat foals.

Do Propylene Glycol, Benzyl Alcohol, and Ethanol in Concomitant Drugs Influence Clinical Outcomes Following Intravenous Acetaminophen in Critically Ill Neonates?

Propylene glycol (PG) and benzyl alcohol (BA) have been shown to inhibit the metabolizing enzyme for acetaminophen in the liver. Ethanol has unpredictable effects on acetaminophen metabolism. Critically ill neonates commonly receive drug formulations containing PG, BA, and ethanol as excipients. Until now, there have been no reports on the influence of BA, PG, and ethanol as excipients in patients undergoing concomitant acetaminophen therapy. We devised the present study to evaluate whether any significant differences in plasma acetaminophen concentrations, liver function tests, and serum creatinine exist between neonates receiving excipients containing drugs compared to those without. We included neonates that were administered intravenous acetaminophen with at least one concomitant drug containing either BA, PG, or ethanol as excipients. Plasma acetaminophen concentrations and levels of liver function were evaluated using tests. The doubling of alanine aminotransferase levels was considered to be a marker of hepatotoxicity. Elevation of serum creatinine >1.5 times higher than the baseline value was considered to be indicative of an acute kidney injury. Fifty-seven neonates were recruited in the study. No significant differences in the serum acetaminophen concentrations, liver and renal function tests, and rates of successful closure of ductus arteriosus were observed between the groups. No significant changes in the serum acetaminophen levels and the clinical outcomes were observed due to the presence of BA, PG, or ethanol in concomitant drugs as excipients. Probably, drugs containing these excipients can be safely administered, and even formulations containing these excipients with acetaminophen are likely to be safe for critically ill neonates.

Pharmacokinetics of acetaminophen after a single Oral administration of 20 or 40 mg/kg to 7-9 Day-old foals.

Acetaminophen is utilized in human infants for pain management and fever. Neonatal foals might benefit from administration of acetaminophen but effective and safe dosage regimens for neonatal foals remains to be determined. The objective was to determine the plasma pharmacokinetics of acetaminophen following oral administration of a single dose of 20 mg/kg or 40 mg/kg to neonatal foals. A secondary objective was to evaluate any changes in hematology and biochemistry profiles. Randomized study. Eight clinically healthy 7-9-day old Quarter Horse foals (3 colts and 5 fillies) received a single oral dose of acetaminophen either 20 (n = 4) or 40 (n = 4) mg/kg. Hematology and biochemistry profiles were evaluated before and 7 days after drug administration. Blood samples were collected before and 8 times after acetaminophen administration for 48 h to quantify plasma acetaminophen concentrations. Plasma pharmacokinetic parameters were estimated using non- compartmental analysis. The median peak plasma concentrations (and range) occurred at 1.5 (0.5-2) hours, and 1.0 (1-2) hours for the 20 and 40 mg/kg doses. The maximum plasma concentration (and range) was 12 (7.9-17.4) μg/mL for the 20 mg/kg dose and 14 (11-18) μg/mL for 40 mg/kg dose. The median AUC0-∞ ranged from 46 to 100 and 79 to 160 h*-μg/mL for the 20 and 40 mg/kg dose, respectively. Hematology and biochemistry profiles remained within normal limits. Plasma disposition of acetaminophen after oral administration of 20 and 40 mg/kg to neonates is comparable to adult horses. However, safety and the optimal dosage regimen of acetaminophen for treating pain and or pyrexia in neonates in this age group remains to be determined.

Pharmacokinetics of single dose administration of three increasing doses of acetaminophen per os in 1-3-month-old foals.

Acetaminophen is a common analgesic and antipyretic drug used in human medicine and might be an alternative to nonsteroidal anti-inflammatory drugs for treating pain and pyrexia in foals. The pharmacokinetics and safety of differing doses of acetaminophen have not been investigated in foals. To determine the plasma pharmacokinetics and any changes in haematology and biochemistry profiles following oral administration of single doses of acetaminophen at 10, 20, and 40 mg/kg to foals. Randomised cross-over pharmacokinetic study. Six Quarter Horse (two colts and four fillies) foals received 10, 20, and 40 mg/kg acetaminophen orally once. Haematology and biochemistry profiles were performed before and 7 days after each drug administration. Blood samples were collected over 64 h after drug administration and were used to quantify plasma acetaminophen concentrations by liquid chromatography. Pharmacokinetic parameters were determined using compartmental analysis. Median (range) acetaminophen plasma concentrations were 4.4 (1.8-5.1), 6.3 (2.6-12.6), and 14 (7.3-18)μg/ml for the 10, 20, and 40 mg/kg doses, respectively. Median acetaminophen area under the concentration versus time curve (AUC)0-∞ ranged from 25 (11-32), 41 (22-74), and 105 (82-142)h × μg/ml for the 10, 20, and 40 mg/kg doses, respectively. Dose-normalised maximal concentrations and AUC0-∞ values were similar across dose concentrations (p > 0.05). Median terminal half-life for all doses was 2.7-2.8h. Haematology and biochemistry profiles were normal except for blood urea nitrogen and alkaline phosphatase concentrations. Foals were growing throughout the study, starting at 1month and ending at 3months. Deposition of drugs changes with age. The sample size was small and only single doses were evaluated. No liver biopsies were performed. Plasma disposition of acetaminophen after a single oral dose of 10, 20, and 40 mg/kg to 1-3-month-old foals varies greatly with the dose. The analgesic and antipyretic effect in foals is unknown.

Effects of housing environment on oral absorption of acetaminophen in healthy Beagles.

To evaluate the effects of housing environment on oral absorption of acetaminophen in dogs. 6 healthy Beagles. Acetaminophen (325 mg, PO; mean dose, 31.1 mg/kg) was administered in a crossover study design with dogs housed in their normal environment or in a cage in an unfamiliar environment. There was a 7-day washout period between phases. Blood samples were collected for 24 hours following acetaminophen administration, and plasma acetaminophen concentrations were determined with high-pressure liquid chromatography. A 2-compartment model with lag time was the best fit for both phases of the study. None of the primary or secondary pharmacokinetic parameters were significantly different between the 2 housing environments. Findings suggested that in dogs, housing environment (normal environment vs a cage in an unfamiliar environment) did not significantly affect oral absorption and, by extension, gastric emptying of acetaminophen.

Comparison of the effects on lameness of orally administered acetaminophen-codeine and carprofen in dogs with experimentally induced synovitis.

To compare the ability of acetaminophen-codeine (AC; 15.5 to 18.5 mg/kg and 1.6 to 2.0 mg/kg, respectively) or carprofen (4.2 to 4.5 mg/kg) administered PO to attenuate experimentally induced lameness in dogs. 7 purpose-bred dogs. A blinded crossover study was performed. Dogs were randomly assigned to receive AC or carprofen treatment first and then the alternate treatment a minimum of 21 days later. Synovitis was induced in 1 stifle joint during each treatment by intra-articular injection of sodium urate (SU). Ground reaction forces were assessed, and clinical lameness was scored at baseline (before lameness induction) and 3, 6, 9, 12, 24, 36, and 48 hours after SU injection. Plasma concentrations of acetaminophen, carprofen, codeine, and morphine were measured at various points. Data were compared between and within treatments by repeated-measures ANOVA. During AC treatment, dogs had significantly higher lameness scores than during carprofen treatment at 3, 6, and 9 hours after SU injection. Peak vertical force and vertical impulse during AC treatment were significantly lower than values during carprofen treatment at 3, 6, and 9 hours. Plasma concentrations of carprofen (R)- and (S)-enantiomers ranged from 2.5 to 19.2 μg/mL and 4.6 to 25.0 μg/mL, respectively, over a 24-hour period. Plasma acetaminophen concentrations ranged from 0.14 to 4.6 μg/mL and codeine concentrations from 7.0 to 26.8 ng/mL, whereas plasma morphine concentrations ranged from 4.0 to 58.6 ng/mL. Carprofen as administered was more effective than AC at attenuating SU-induced lameness in dogs.

Effect of replacing lactose with fat in milk replacer on abomasal emptying and glucose–insulin kinetics in male dairy calves

ABSTRACT Objective Altering energy supply and the relative proportions of energy source in the first weeks of life of dairy calves may influence glycemic and insulinemic responses. The objective of this study was to assess the metabolic responses to high-lactose or high-fat milk replacer. Materials and Methods Forty male calves were fed 7 L of milk replacer per day in 2 meals given 10 h apart, considered either high lactose (44% lactose, HL) or high fat (37% lactose, HF), from the first week of life to 30 d of age. Postprandial blood plasma glucose, insulin, and acetaminophen (an abomasal emptying marker) concentrations were measured up to 420 min and used to fit a mathematical model of abomasal emptying and glucose–insulin dynamics. Additionally, an i.v. glucose tolerance test was used to assess glucose tolerance and insulin sensitivity. Results and Discussion Insulin sensitivity remained unchanged; however, glucose maximal concentration and change from baseline tended to be greater for HL in response to an i.v. glucose challenge. Postprandial glucose was elevated at 30 min for HL and HF at 60 and 90 min. Model parameterization showed no difference in abomasal emptying; however, intestinal glucose absorption tended to be faster with HL. Potentiation of insulin action was greater with HL, and pancreatic responsiveness tended to be greater with HF. Implications and Applications These results suggest HL increased early-phase postprandial glucose appearance, which may influence insulin action. In this study, modifying milk replacer composition to more closely resemble cow’s milk did not negatively affect glucose metabolism.

Effect of tulathromycin on abomasal emptying rate in healthy lactating goats

Tulathromycin is a long-acting semi-synthetic macrolide antibiotic that is synthesized from erythromycin. Macrolides have pharmacodynamic properties beyond their antimicrobial effects, including anti-inflammatory and immunomodulatory properties that are perceived to be clinically beneficial. An additional pharmacodynamic property of macrolides is a prokinetic effect, which is marked in adult cattle and calves administered erythromycin and less prominent in calves administered spiramycin, tilmicosin, and tylosin. Based on structural similarities to erythromycin, the hypothesis was that parenteral administration of tulathromycin would increase abomasal emptying rate in healthy adult goats. Accordingly, five adult lactating goats (30–36 months of age) received each of the following 3 treatments: IM injection of 2mL of 0.9% NaCl (control); IM injection of tulathromycin (2.5mg/kg body weight); IV injection of tulathromycin (2.5mg/kg body weight). Abomasal emptying rate was assessed by acetaminophen absorption, which was injected into the abomasum through a surgically placed abomasal cannula at 50mg/kg BW, 15min after each treatment. Jugular venous blood samples were obtained periodically after injection and plasma acetaminophen concentrations determined using a colorimetric nitration assay. The maximum observed plasma acetaminophen concentration (Actual Cmax) and time of actual Cmax (Actual Tmax) were determined, and pharmacokinetic modeling was used to calculate model Cmax and model Tmax and abomasal emptying half-time (T50). Results showed that tulathromycin (IM and IV) increased abomasal emptying rate, as indicated by a shorter time to actual Tmax and model Tmax, and shorter T50, than control. The clinical relevance of these findings remains to be determined.

Unexpected Late Rise in Plasma Acetaminophen Concentrations with Change in Risk Stratification in Acute Acetaminophen Overdoses

BackgroundThe acetaminophen risk analysis nomogram is used to predict hepatotoxicity risk in acute acetaminophen overdose based on a single plasma acetaminophen concentration (PAC) measured between 4 and 24 h after ingestion. There are case reports of patients with acute overdoses of acetaminophen combination products in whom a toxic PAC occurred later after an initial non-toxic PAC at approximately 4 h. ObjectivesThe objective was to describe patients who had an initial non-toxic PAC and a subsequent toxic PAC. MethodsA poison center’s database was searched for records in which patients were administered N-acetylcysteine. Cases were included if they involved an acute overdose of an acetaminophen-containing product with at least 2 plottable PACs, the first of which was obtained at least 4 h after ingestion and was below the treatment line on the nomogram with a subsequent toxic PAC. Data were analyzed for doses, timed PACs, specific acetaminophen preparation, coingestants, activated charcoal administration, and clinical effects. ResultsTwenty patients were included. Thirteen patients ingested combination products. All patients experienced vomiting, neurologic, or cardiovascular effects at presentation or before obtaining the second PAC. Two patients developed hepatotoxicity, one of which died from the complications of acetaminophen-induced hepatotoxicity. ConclusionThe nomogram fails to predict toxicity based on a single PAC in a small subset of patients.

Intravenous acetylcysteine for the treatment of acetaminophen overdose

Importance of the field: Acetaminophen is a leading cause of overdose-related hepatotoxicity. Although acetylcysteine prevents or minimizes acetaminophen-induced hepatotoxicity and reduces mortality, some patients presenting with complicated overdose scenarios (massive ingestions or combination or modified-release formulations) may develop toxicity despite administration of recommended dosage regimen.Areas covered in this review: The article evaluates evidence regarding intravenous acetylcysteine's effectiveness in patients with acute overdoses who receive treatment within 10 h or > 10 h, patients with chronic supratherapeutic ingestions, and those with acetaminophen-induced fulminant hepatic failure. Intravenous and oral acetylcysteine are compared.What the reader will gain: A one-size-fits-all approach towards acetylcysteine therapy provides suboptimal care in some patients. High-risk patients are identified. Specific discontinuation criteria are presented.Take home message: The standard intravenous regimen will effectively treat most early-presenting uncomplicated overdoses. Acetylcysteine dosing should be individualized in patients with complicated presentations and in particular situations in which plasma acetaminophen concentrations may be persistently elevated at the end of the infusion or in late presenters. More studies are needed to evaluate the optimal intravenous dosage regimen and the role of oral acetylcysteine in these high-risk patients. Treatment decisions may be aided by consultation with a poison center and/or clinical toxicologist.

Assessment of the acetaminophen absorption test as a diagnostic tool for the evaluation of the reticular groove reflex in lambs

To assess the acetaminophen absorption test (APAT) for use in determining function of the reticular groove reflex in lambs. 12 Baluchi lambs. 2 consecutive APATs were performed at each of 3 developmental stages (stage 1, before weaning; stage 2, at weaning; and stage 3, after weaning). Lambs suckled a test solution consisting of acetaminophen and barium sulfate and 1 week later were tube fed the same test solution. Abdominal radiographs were obtained immediately after administration of the test solution. Plasma acetaminophen concentrations were determined before and 30, 60, 90, 120, 150, and 180 minutes after intake of the test solution. Closure of the reticular groove after suckling the test solution was confirmed in all 12 lambs at stage 1, in 8 lambs at stage 2, and in 0 lambs at stage 3. Maximum plasma acetaminophen concentrations and area under the plasma acetaminophen concentration-time curves from 0 to 180 minutes were significantly higher in lambs suckling the test solution, compared with values for tube-fed lambs. Receiver operating characteristics analysis revealed that the plasma acetaminophen concentration at 60 minutes after administration was best suited to determine closure of the reticular groove in lambs. Results suggested that the APAT can be a useful diagnostic instrument to assess function of the reticular groove reflex in lambs. We propose a cutoff value for the plasma acetaminophen concentration of 25 microg/mL at 60 minutes after administration to determine function of the reticular groove mechanism in lambs.

Influence on platelet aggregation of i.v. parecoxib and acetaminophen in healthy volunteers

Acetaminophen (paracetamol) alone or in combination with other analgesics is widely used for postoperative analgesia. While acetaminophen and non-steroidal anti-inflammatory drugs inhibit platelet function, the cyclooxygenase-2 (COX-2) selectively inhibiting coxibs show no interference with platelet function. The authors studied the effect of a combination of i.v. parecoxib and acetaminophen on platelet function in healthy volunteers. Eighteen healthy, male volunteers (22-33 yr) received i.v. acetaminophen 1 g, parecoxib 40 mg+acetaminophen 1 g or placebo in a double-blind, crossover study. Platelet function was assessed by photometric aggregometry and by measuring the release of thromboxane B(2). Plasma acetaminophen concentrations were measured by high-performance liquid chromatography. Platelet aggregation (median area under the curve) triggered with arachidonic acid 500 microM was 24.6, 3.9 and 4.2x10(3) area units (P=0.02, all groups) after placebo, acetaminophen and parecoxib+acetaminophen, respectively. Inhibition of platelet aggregation showed no difference between acetaminophen alone and the combination (P=0.82). Aggregation triggered with arachidonic acid 750 or 1000 microM, adenosine diphosphate (ADP) 1.5 or 3 microM, or epinephrine 5 microM showed no differences between the groups. Release of thromboxane B(2) in response to ADP was inhibited similarly by both acetaminophen and the combination. Plasma acetaminophen concentrations were similar after acetaminophen and the combination. Acetaminophen and parecoxib showed no interaction in inhibiting platelet function. In combination they cause a mild degree of COX-1 inhibition corresponding to that of acetaminophen alone.

Influence of acetaminophen at therapeutic doses on surrogate markers of severity of acute viral hepatitis

Data on the influence of acetaminophen intake on acute viral hepatitis is scarce, but it could play a role in the worsening of this disease. The aim of this study was to determine whether the intake of acetaminophen at therapeutic doses affects the severity of acute viral hepatitis. This was a prospective study concerning 37 consecutive patients hospitalized for acute viral hepatitis. Acetaminophen consumption and time since last intake were assessed by a questionnaire. Parameters of severity were studied in comparison to time related serum concentrations of acetaminophen. Patients hospitalized for acute viral hepatitis (18 male, 19 female patients) had a mean age of 29.2 +/- 11.5 years. The causal virus was HAV (n=23), HBV (n=7) and other viruses (n=8). The mean cumulated dose of acetaminophen was 7.7 +/- 5.65 g. The daily dose did not exceed the therapeutic dosage and the mean was 1.95 +/- 0.81 g (1-3 g). Patients who received 7.5 g of acetaminophen or more had a lower prothrombin index 52.4 +/- 30.3% vs 74.2 +/- 17.2% (P=0.039), and a lower factor V 54.7 +/- 33.2% vs 83.3 +/- 19.6% (P=0.033). Prothrombin index and bilirubinemia were negatively correlated with time related plasma acetaminophen concentrations. The use of acetaminophen at therapeutic doses was associated with greater alterations of surrogate markers of the severity of acute viral hepatitis especially hepatitis A. This was related to cumulated dosages and correlated to the time related acetaminophen plasma concentrations. Acetaminophen use should be interrupted when acute hepatitis is suspected.

Measurement of Serum Acetaminophen–Protein Adducts in Patients With Acute Liver Failure

Acetaminophen toxicity is the most common cause of acute liver failure (ALF) in the United States and Great Britain, but may be underrecognized in certain settings. Acetaminophen-protein adducts are specific biomarkers of drug-related toxicity in animal models and can be measured in tissue or blood samples. Measurement of serum adducts might improve diagnostic accuracy in acute liver failure (ALF) patients. We measured serum acetaminophen-protein adducts using high-pressure liquid chromatography with electrochemical detection in coded sera of 66 patients with ALF collected prospectively at 24 US tertiary referral centers. Samples were included from 20 patients with well-characterized acetaminophen-related acute liver failure, 10 patients with ALF owing to other well-defined causes, 36 patients with ALF of indeterminate etiology, and 15 additional patients without ALF but with known acetaminophen overdose and minimal or no biochemical liver injury. Acetaminophen-protein adducts were detected in serum in 100% of known acetaminophen ALF patients and in none of the ALF patients with other defined causes, yielding a sensitivity and specificity of 100%. In daily serial samples, serum adducts decreased in parallel with aminotransferase levels. Seven of 36 (19%) indeterminate cases demonstrated adducts in serum suggesting that acetaminophen toxicity caused or contributed to ALF in these patients. Low adduct levels were present in 2 of 15 patients with acetaminophen overdose without significant liver injury. Measurement of serum acetaminophen-protein adducts reliably identified acetaminophen toxicity, and may be a useful diagnostic test for cases lacking historical data or other clinical information.

Dose-dependent Inhibition of Platelet Function by Acetaminophen in Healthy Volunteers

Acetaminophen (paracetamol) is widely used for postoperative analgesia. Its mechanism of action is inhibition of prostaglandin synthesis in the central nervous system, and acetaminophen is traditionally not considered to influence platelet function. The authors studied the dose-dependent inhibition of platelet function by acetaminophen in healthy volunteers. Thirteen healthy male volunteers (aged 19-26 yr) were given placebo or 15, 22.5, or 30 mg/kg acetaminophen intravenously in a double-blind, crossover study. Ten and 90 min after infusion, platelet function was assessed by photometric aggregometry and by measuring release of thromboxane B2, analgesia by cold pressor test, and plasma acetaminophen concentrations by high-performance liquid chromatography. When triggered with 500 microm arachidonic acid, median platelet aggregation (area under the curve) was 25.7, 22.8, 4.1, or 3.6 x 10 area units (P < 0.001) 10 min after placebo or 15, 22.5, or 30 mg/kg acetaminophen, respectively. An increasing concentration of arachidonic acid attenuated the antiaggregatory effect. After 90 min, platelet function was recovering. Release of thromboxane B2 was also dose-dependently inhibited by acetaminophen. Although plasma concentration of acetaminophen increased linearly with the dose, no analgesic effect was detected in the cold pressor test. Acetaminophen, which is a weak inhibitor of platelet cyclooxygenase 1, has a dose-dependent antiaggregatory effect. This property may become clinically significant in patients with intrinsic or drug-induced impairment of hemostasis.

Pharmacokinetics of an Oral Drug (Acetaminophen) Administered at Various Times in Relation to Subcutaneous Injection of Exenatide (Exendin‐4) in Healthy Subjects

Exenatide is an incretin mimetic with potential glucoregulatory activity in type 2 diabetes. This randomized, single-blind, placebo-controlled 6-way crossover study assessed exenatide's effect on acetaminophen pharmacokinetics. Of 40 randomized healthy subjects, 39 completed the study. On the placebo day, acetaminophen (1000 mg) was ingested and placebo injected subcutaneously at 0 hours. On exenatide days, acetaminophen was ingested at -1, 0, +1, +2, and +4 hours, relative to the 10 mug exenatide injected subcutaneously at 0 hours. With exenatide injection, mean plasma acetaminophen AUC(0-12 h) values were reduced by 11% to 24% (vs placebo). Peak plasma acetaminophen concentrations were similar for the -1-hour and placebo groups and reduced by 37% to 56% at other times. The most frequent adverse events were generally mild to moderate nausea and vomiting. Exenatide treatment concurrent with or preceding acetaminophen ingestion slowed acetaminophen absorption but had minimal effect on the extent of absorption.

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.

Effect of Histamine H2-receptor Antagonists on Acetaminophen and its Metabolites in Human Plasma

The effect of histamine H2-receptor antagonists on plasma concentrations of acetaminophen was investigated with respect to hepatic metabolism.Acetaminophen (1000 mg) was administered orally together with ranitidine (300 mg), nizatidine (300 mg), nizatidine (150 mg) or placebo to five healthy male volunteers. Venous blood samples were taken before and after administration and plasma acetaminophen and acetaminophen conjugates (glucuronide and sulphate) were measured by high-performance liquid chromatography. The pharmacokinetic parameters were calculated from the plasma acetaminophen concentration-time curves for each volunteer.With ranitidine, compared with placebo, plasma acetaminophen concentrations were significantly increased from 15 to 120 min. and plasma acetaminophen glucuronide conjugate concentrations were significantly decreased from 15 to 45 min. With nizatidine, as compared with placebo, plasma acetaminophen concentrations were significantly increased from 45 to 120 min. and 45 to 60 min. for the high and low doses of the drug, respectively. Acetaminophen glucuronide concentrations were significantly decreased from 30 to 45 min. and at 30 min., respectively, for the high and low doses of nizatidine, respectively. However, with ranitidine and nizatidine, plasma acetaminophen sulphate concentrations were not significantly altered.Co-administration with ranitidine or nizatidine reduces plasma acetaminophen glucuronide concentrations and increases plasma acetaminophen concentrations dose-dependently. These effects of ranitidine and nizatidine could result from inhibi-tion of glucuronyltransferase. Therefore, care is necessary when administering acetaminophen together with ranitidine or nizatidine.

Pharmacokinetics of acetaminophen in Hong Kong Chinese subjects

The pharmacokinetics of acetaminophen have been well studied in different populations, especially in Caucasians. However, limited studies on acetaminophen pharmacokinetics have been conducted in the native Chinese and few such data have been reported in the English language literature. Previous published studies suggested that environmental and genetic factors may cause inter-individual difference in acetaminophen disposition, thus we investigated the pharmacokinetics of acetaminophen in Hong Kong Chinese subjects. A single 500 mg oral dose of acetaminophen was administered to 12 healthy male Chinese subjects under fasting conditions. Multiple blood samples were obtained after drug administration. Plasma acetaminophen concentrations were determined using HPLC, and its main pharmacokinetic parameters were generated. In comparison to other published data, acetaminophen half-life was considerably longer (15–62%), and oral clearance was lower (16–56%) in Hong Kong Chinese as compared to Australian Chinese, Caucasians (USA, UK, Australia), and subjects from Pakistan, Denmark, Spain and South Africa. Similarities however were found in the pharmacokinetic parameters between Hong Kong Chinese and Mainland Chinese subjects. The observed pharmacokinetic parameters of acetaminophen in Hong Kong Chinese subjects may be different from other ethnic populations. Further studies are needed to verify this hypothesis.

Current Literature: Sequential Single Doses of Cisapride, Erythromycin, and Metoclopramide in Critically III Patients Intolerant to Enteral Nutrition: A Randomized, Placebo‐controlled, Crossover Study

Objective: To evaluate the comparative efficacy of enteral cisapride, metoclopramide, erythromycin, and placebo for promoting gastric emptying in critically ill patients with intolerance to gastric enteral nutrition (EN). Design: A randomized, crossover study. Setting: Adult medical intensive care unit at a university‐affiliated private hospital and trauma intensive care unit at a university teaching hospital. Patients: Ten adult, critically ill, mechanically ventilated patients not tolerating a fiber‐containing EN product defined as a single aspirated gastric residual volume &gt;150 mL or two aspirated gastric residual volumes &gt;120 mL during a 12‐hour period. Interventions: Patients received 10 mg of cisapride, 200 mg of erythromycin ethylsuccinate, 10 mg of metoclopramide, and placebo as 20 mL of sterile water every 12 hours over 48 hours. Acetaminophen solution (1000 mg) was administered concurrently. Gastric residual volumes were assessed, and plasma acetaminophen concentrations were serially determined by TDx between 0 and 12 hours to evaluate gastric emptying. Measurements and Main Results: Gastric residual volumes during the study were not significantly different between agents. No differences in area under the concentration vs. time curve or elimination rate constant were identified between agents. Metoclopramide and cisapride had a significantly shorter mean residence time of absorption than erythromycin (6.3 ± 4.5 [SEM] mins and 10.9 ± 5.8 vs. 30.1 ± 4.5 mins, respectively [p &lt; .05]). Metoclopramide (9.7 ± 15.3 mins) had a significantly shorter time to peak concentration compared with erythromycin and placebo (60.7 ± 8.1 and 50.9 ± 13.5 mins, respectively [p &lt; .05]). The time to onset of absorption was significantly shorter for metoclopramide vs. cisapride (5.7 ± 4.5 vs. 22.9 ± 5.7 mins [p &lt; .05]). Conclusion: In critically ill patients intolerant to EN, single enteral doses of metoclopramide or cisapride are effective for promoting gastric emptying in critically ill patients with gastric motility dysfunction. Additionally, metoclopramide may provide a quicker onset than cisapride. (Crit Care Med 28:438–44, 2000)