Plasma Acetaminophen Concentration Research Articles

Effect of Saffron (Crocus sativus L.), as a Bioenhancer, on Pharmacokinetic of Acetaminophen: An Animal Study

In Traditional Persian Medicine (TPM) saffron is used as an accompaniment agent “Mobadreq” in polyherbal formulations. According to TPM texts, “Mobadreq” is a substance (or drug) which facilitates access of drugs or food to the whole body or specific organs. This study investigated the effect of oral co-administration of Crocus sativus L. (saffron) on the absorption and some pharmacokinetic parameters of acetaminophen in rats. Two groups of rats (n=6) were treated by 1: acetaminophen 10 mg/kg along with Crocus sativus 4 mg/kg (test group) and 2: 10 mg/kg acetaminophen (control). The plasma concentrations of acetaminophen after oral administration (at 0, 5, 10, 15, 20, 40, 60, 90, and 120 min) were monitored by an HPLC-UV method. Results indicated that the plasma concentration of acetaminophen in the test group was reached to the maximum concentration (Cmax) faster than control group. As a result, at 5 to 40 minutes after drug gavage, the concentration of acetaminophen in both groups was significantly different. It was also found that co-administration of acetaminophen and saffron significantly increased acetaminophen’s area under concentration curve (AUC0-60) in comparison to the acetaminophen alone (p<0.025). These results suggest that saffron could increase the absorption rate of acetaminophen. Consequently, saffron can be considered and introduced as an enhancer of absorption rate and efficacy of acetaminophen and other drugs at least by oral route although the drug interactions with this herb should be considered.

Development of Sustained Release System Based on High Water-Absorbable Gel Formation Using Croscarmellose Sodium, Alkaline Excipients and HPMC (ACSH SR System); Novel Application of Croscarmellose Sodium as a Gel Former.

Croscarmellose sodium, generally used as a superdisintegrant in pharmaceutical formulations, is hydrolyzed to form the gel structure under basic pH conditions. Utilizing this property of croscarmellose sodium, we developed a novel sustained release (SR) system. Immediate release (IR) and SR tablets containing croscarmellose sodium, alkaline excipients and/or hydroxypropyl methylcellulose (HPMC) were prepared and examined for wet strength and in vitro drug release behavior. In vivo oral drug absorption was evaluated for IR tablets, HPMC tablets and our novel SR tablets in fasted Beagle dogs. To form the gel structure even under the physiological condition, alkaline excipients were added into the formulation containing croscarmellose sodium. Furthermore, HPMC was used to make the gel structure strong enough against mechanical destructive forces. The novel alkalized croscarmellose sodium-HPMC (ACSH) SR tablet, consisting of croscarmellose sodium, alkaline excipients, and HPMC, successfully sustained the release of acetaminophen, ibuprofen, or nicardipine hydrochloride, compared with the IR tablets. The ACSH SR system provided a better release of acetaminophen than the HPMC tablet without croscarmellose sodium in the release study using a small volume of liquid, suggesting that substantial release and subsequent absorption would be expected in the distal intestinal segments after oral dosing. The in vivo oral absorption study revealed that the ACSH SR system successfully suppressed and prolonged the plasma concentrations of acetaminophen. This novel ACSH SR system prepared with croscarmellose sodium, alkaline excipients, and HPMC, would be a promising SR formulation for enabling substantial drug absorption in the distal intestinal segments.

Pharmacokinetics, clinical efficacy and safety of acetaminophen (paracetamol) in adult horses with naturally occurring chronic lameness.

Acetaminophen is used clinically in horses with musculoskeletal pain; however, no studies have been performed in horses with chronic lameness. To determine the pharmacokinetics, safety and efficacy of chronic dosing of acetaminophen in horses with naturally occurring chronic lameness. Longitudinal. Twelve adult horses with chronic lameness were treated with acetaminophen (30 mg/kg PO) every 12 h for 21 days. Plasma concentrations of acetaminophen were analysed on days 7 and 21 via LC-MS/MS and noncompartmental pharmacokinetic analysis. Lameness was evaluated by body-mounted inertial sensor (BMIS) and 10-point subjective lameness score on day 21 and compared to untreated baseline evaluation on day 35. Clinicopathological analysis (n = 12), hepatic biopsy (n = 6) and gastroscopy (n = 6) were evaluated on days -1 and 22. Maximum plasma acetaminophen concentration (Cmax ) was 20.83 ± 10.25 μg/mL at time (Tmax ) 0.40 ± 0.22 h on day 7. The Cmax on day 21 was 17.33 ± 6.91 μg/mL with a Tmax of 0.67 ± 0.26 h. Subjective lameness scores significantly improved at 2 and 4 h post-treatment; Significant percent improvement was detected in PDmax for horses with hindlimb lameness at 1, 2 and 8 h post-treatment. There were no significant differences in gastroscopy or hepatic biopsy scores between days -1 and 22. Small sample size, multi-limb lameness of varying severity and aetiology, lack of intermediary lameness evaluation. In horses with naturally occurring chronic lameness, acetaminophen at 30 mg/kg produced a transient improvement in subjective lameness and BMIS evaluation. Acetaminophen may not be effective as a monotherapy. Acetaminophen was safe following 21 days of 30 mg/kg PO every 12 h, with no evidence of clinically significant changes in clinicopathological analysis, hepatic biopsy or gastric ulceration scores.

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.

Intravenous Acetaminophen Does Not Provide Adequate Postoperative Analgesia in Dogs Following Ovariohysterectomy.

Simple SummaryAcetaminophen is the most commonly used pain relief (analgesic) agent in humans worldwide and its use is becoming more frequent in dogs. However, limited evidence supports this use. This study aimed to investigate the analgesic effect of acetaminophen when administered as an intravenous injection post-operatively in female dogs. A total of 34 dogs were randomly divided into two groups and either administered acetaminophen or saline intravenously immediately after desexing. The dogs had their pain levels evaluated at 10, 20, 40, 60, 120, and 180 min after awakening from general anesthesia and the pain levels between groups were compared. Concurrently, the dogs had blood collected at 2, 5, 10, 40, and 80 min following injection of the acetaminophen. The blood was analyzed to quantify the levels of acetaminophen in the body. This study found that acetaminophen was no better than saline in providing analgesia in dogs following surgery. This study suggests that acetaminophen used alone may not be an appropriate post-operative analgesic agent for desexing procedures.(1) Objective: To investigate the analgesic effects of intravenous acetaminophen after intravenous administration in dogs presenting for ovariohysterectomy. (2) Methods: 14 ASA I client-owned female entire dogs. In this randomized, blinded, clinical study, dogs were given meperidine and acepromazine intramuscularly before induction of anesthesia with intravenous propofol. Anesthesia was maintained with isoflurane in oxygen. Intravenous acetaminophen 20 mg/kg or 0.9% NaCl was administered postoperatively. Pain assessments were conducted using the Glasgow Pain Scale short form before premedication and at 10, 20, 60, 120, and 180 min post-extubation or until rescue analgesia was given. The pain scores, times, and incidences of rescue analgesia between the groups was compared. Blood was collected before and 2, 5, 10, 20, 40, and 80 min after acetaminophen administration. Acetaminophen plasma concentration was quantified by liquid chromatography-mass spectrometry. The acetaminophen plasma concentration at the time of each pain score evaluation was subsequently calculated. (3) Results: There was no significant difference in pain scores at 10 min, highest pain scores, or time of rescue analgesia between groups. In each group, 3 dogs (43%) received rescue analgesia within 20 min. (4) Conclusions: Following ovariohysterectomy in dogs, there was no detectable analgesic effect of a 20 mg/kg dosage of intravenous acetaminophen administered at the end of surgery.

Gender Variations in Pharmacokinetics of Paracetamol in Hausa/Fulani Ethnic group in Northwest Nigeria - A Two-stage Approach.

Background:Paracetamol is one of the most commonly used drugs worldwide and has been linked to drug-related liver damage, even when taken at recommended doses. Ingesting the upper limit of recommended doses of the drug produced a doubling of mortality when compared to not taking the drug. Acetaminophen ingestion has been implicated in the development of angioedema, the exasperation of asthma, and urticaria in patients with aspirin intolerance.Aim:This study aimed at assessing gender variations in the pharmacokinetics of paracetamol in Hausa/Fulani, the most populous ethnic group in Nigeria and determines a possibility of toxicity in the group.Methods:It was an exploratory study involving twenty participants selected by criterion sampling who satisfied inclusion criteria. They were fasted 11-h preceding acetaminophen administration to 3 h after administration. A single dose of acetaminophen, 1 g orally with 300 ml of distilled water, was administered at 8 A. M. Blood was obtained before the administration and 15, 30, and 45 min, and 1, 2, 3, 4, 5, and 6 h after the administration. Acetaminophen plasma concentrations were determined by validated reverse-phase high-performance liquid chromatography Food and Drug Administration guidelines.Results:Six out of 19 (31.6%) participants have higher than maximum therapeutic plasma concentration (>20 μg/ml). Pharmacokinetics parameters were higher in males except for clearance and volume of distribution.Conclusion:Clearance from the plasma tends to be more for females than their male counterparts. A good proportion of Hausa/Fulani is prone to acetaminophen toxicity at a therapeutic dose.

Plasma and hepatic concentrations of acetaminophen and its primary conjugates after oral administrations determined in experimental animals and humans and extrapolated by pharmacokinetic modeling

Plasma concentrations of acetaminophen, its glucuronide and sulfate conjugates, and cysteinyl acetaminophen were experimentally determined after oral administrations of 10 mg/kg in humanised-liver mice, control mice, rats, common marmosets, cynomolgus monkeys, and minipigs; the results were compared with reported human pharmacokinetic data. Among the animals tested, only rats predominantly converted acetaminophen to sulfate conjugates, rather than glucuronide conjugates. In contrast, the values of area under the plasma concentration curves of acetaminophen, its glucuronide and sulfate conjugates, and cysteinyl acetaminophen after oral administration of acetaminophen in marmosets and minipigs were consistent with those reported in humans under the present conditions. Physiologically based pharmacokinetic (PBPK) models (consisting of the gut, liver, and central compartments) for acetaminophen and its primary metabolite could reproduce and estimate, respectively, the plasma and hepatic concentrations of acetaminophen in experimental animals and humans after single virtual oral doses. The values of area under the curves of hepatic concentrations of acetaminophen estimated using PBPK models were correlated with the measured levels of cysteinyl acetaminophen (a deactivated metabolite) in plasma fractions in these species. Consequently, using simple PBPK models and plasma data to predict hepatic chemical concentrations after oral doses could be helpful as an indicator of in vivo possible hepatotoxicity of chemicals such as 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.

Pharmacokinetics of acetaminophen after intravenous and oral administration in fasted and fed Labrador Retriever dogs.

Acetaminophen (paracetamol) is used in dogs to manage fever and mild pain. The aim of this study was to assess the pharmacokinetics of acetaminophen in both fed and fasted Labrador Retrievers after a single intravenous and oral administration (20mg/kg). Six healthy dogs underwent three treatments in a randomized block study (a, n=2; b, n=2; c, n=2). In phase one, group a received acetaminophen intravenously, group b and c orally after being fasted and fed, respectively. In phase two and three, groups were swapped, and the experiment was repeated. At the end of the trial, each dog received the same treatment. Acetaminophen plasma concentrations were detected using a validated HPLC-UV method. The pharmacokinetic analysis was performed using a noncompartmental model. Clearance, volume at steady state and half-life of acetaminophen in Labrador Retrievers were 0.42L/kghr, 0.87L/kg and 1.35hr, respectively. No significant statistical differences were found between fasted and fed dogs regarding maximum plasma concentration, time at maximum concentration and bioavailability as measured by the AUC. Feeding does not significantly affect the acetaminophen oral pharmacokinetics.

Bioavailability of rectal acetaminophen in children following anorectal surgery

BackgroundAcetaminophen is widely used as an analgesic and antipyretic agent in pediatrics.Although bioavailability of rectal acetaminophen is unpredictable, rectal route is a usual and acceptable method of prescription. Major anorectal surgery may alter the normal structure of the surgical site, especially the vascular elements and the normal connections between port and systemic vessels. As a result the pharmacokinetics of rectal medications might also be altered.Based on this hypothesis, we decided to study acetaminophen plasma concentration among children who underwent these types of surgeries to determine the pharmacokinetic of absorption, plasma concentration, safety, and efficacy of rectal acetaminophen. Materials and methodsThe study included 20 cases with previous history of pull-through procedure owing to Hirschsprung's disease (HD), 20 cases with imperforate anus (IA) reconstructive surgeries who were admitted for colostomy closure, and 20 otherwise healthy cases of inguinal herniotomy. Venus blood sampling was done 4, 8 and 12 hrs after a single loading dose of rectal acetaminophen (40 mg/kg), and plasma acetaminophen concentration was compared between groups. ResultsMean serum acetaminophen levels of the HD group were significantly higher than those of the herniotomy group (36.3 ± 6.79, 27.4 ± 8.42, 16.8 ± 7.62 versus 25.9 ± 9.12, 16.7 ± 6.74, 8.1 ± 5.79 (μg/ml) at 4, 8 and 12 hrs after drug administration and P < 0.05). The IA group had higher concentrations of plasma acetaminophen compared to the herniotomy group; however, the p values were not statistically significant. (31.4 ± 10.39, 21.5 ± 9.12, 13.3 ± 6.79 versus 25.9 ± 9.12, 16.7 ± 6.74, 8.1 ± 5.79 (μg/ml) at 4, 8 and 12 hrs after drug administration). Serum concentrations of acetaminophen in IA and HD patients were above the therapeutic range four hours after administering the loading dose (31.4 ± 10.39 and 36.3 ± 6.79 versus 5–20 μg/ml). ConclusionBioavailability of rectal acetaminophen might get altered after major anorectal surgery in children. Rectal acetaminophen should be administered with special caution among infants with history of anorectal operations. Repeated dose of rectal acetaminophen may cause the drug blood concentration to reach toxic levels in these patients. Type of studyProspective comparative study. Level of evidenceLevel II.

A newly validated HPLC–DAD-UV method to study the effects of medicinal plants extracts, fractions and isolate compounds on gastric emptying in rodents

In this study, we developed and validated a chromatographic method by High-performance Liquid Chromatography coupled to Diode-Array Ultraviolet Detector for quantification of acetaminophen in small volumes of plasma. This analytical method is particularly suitable for studies of gastric emptying time and pharmacokinetics in small rodents. Orally administered acetaminophen is promptly and completely absorbed in the intestines, with negligible absorption from the stomach. Owing to these kinetic features, acetaminophen can be used to study gastric emptying. The newly-validated analytical method was employed to investigate whether plants used as anti-dyspeptics in the Brazilian traditional medicine affect the gastric emptying. Lyophilized aqueous extracts from leaves of Baccharis trimera (Less) DC., Asteraceae (carqueja), Maytenus ilicifolia Mart. Ex Reissek, Celastraceae (espinheira-santa) and Lippia alba (Mill.) N.E.Br. ex Britton & P. Wilson, Verbenaceae (erva-cidreira) were administered by gavage to female Wistar rats 30min before a single oral dose of acetaminophen (50mg/kg). L. alba extract (50mg/kg) did not alter acetaminophen plasma concentration versus time curve an indication that it has no effect on gastric emptying. Extracts of B. trimera (50mg/kg) and M. ilicifolia (30 and 50mg/kg, but not 10mg/kg), however, slightly delayed gastric emptying. M. ilicifolia given by intraperitoneal route (30mg/kg) also retarded gastric emptying. In conclusion, the newly-validated analytical method is adequate for studying the effects of medicinal plants on gastric emptying.

Evaluation of a 12-Hour Sustained-Release Acetaminophen (Paracetamol) Formulation: A Randomized, 3-Way Crossover Pharmacokinetic and Safety Study in Healthy Volunteers.

Acetaminophen (paracetamol) is a first‐line treatment for mild and moderate pain. A twice‐daily sustained‐release (SR) formulation may be more convenient for chronic users than standard immediate‐release (IR) acetaminophen. This randomized, 3‐way crossover study evaluated pharmacokinetics and safety of single‐dose 1500‐ and 2000‐mg SR acetaminophen formulations and 2 doses of IR acetaminophen 1000 mg given 6 hours apart in healthy adults (n = 14). Primary outcome was time that plasma acetaminophen concentration was ≥4 μg/mL (TC≥4μg/mL). Key secondary outcomes were area under the plasma concentration–time curve (AUC) from time 0 to time t, when plasma acetaminophen was detectable (AUC0–t), AUC from 0 to infinity (AUC0–inf), and maximum plasma acetaminophen concentration (Cmax). TC≥4μg/mL from 2000‐mg SR acetaminophen was similar to that from 2 doses of IR acetaminophen, whereas TC≥4μg/mL for 1500‐mg SR acetaminophen was significantly shorter than that for IR acetaminophen (P = .004). The extent of acetaminophen absorption from 2000‐mg SR and 2 doses of the IR formulation was similar and within bioequivalence limits with regard to AUC0–12, AUC0–t, and AUC0–inf. The extent of acetaminophen absorption from 1500‐mg SR was significantly lower than that from IR acetaminophen. The 2000‐mg SR represents a potential candidate formulation for 12‐hour dosing with acetaminophen.

Exposure to acetaminophen and all its metabolites upon 10, 15, and 20 mg/kg intravenous acetaminophen in very-preterm infants.

BackgroundExposure to acetaminophen and its metabolites in very-preterm infants is partly unknown. We investigated the exposure to acetaminophen and its metabolites upon 10, 15, or 20 mg/kg intravenous acetaminophen in preterm infants.MethodsIn a randomized trial, 59 preterm infants (24-32 weeks' gestational age, postnatal age <1 week) received 10, 15, or 20 mg/kg acetaminophen intravenously. Plasma concentrations of acetaminophen and its metabolites (glucuronide, sulfate, cysteine, mercapturate, and glutathione) were determined in 293 blood samples. Area under the plasma concentration-time curves (AUC0-500 min) was related to dose and gestational age.ResultsBetween 10 and 20 mg/kg dose, median AUCs of acetaminophen, glucuronide, sulfate, and cysteine increased significantly resulting in unchanged ratios of AUC of metabolite to acetaminophen. The AUC ratio of glucuronide to acetaminophen increased with gestational age, that of sulfate decreased, and the ratio of cysteine and mercapturate remained unchanged.ConclusionWe found a gestational-age-dependent increase in glucuronidation but no evidence for saturation of a specific pathway as there was a proportional increase in exposure of acetaminophen and all metabolites. Compared with adults, very low exposure to glucuronide but higher exposure to sulfate, cysteine, and mercapturate metabolites was found, of which the relevance is not yet known.

Fabrication of Paper-Based Electrochemical Devices and Detection of Acetaminophen

Compact diagnostic devices, known as point-of-care devices, are receiving more interest due to their advantages of instant use, portability and vast applicability. The main value of point-of-care devices is health awareness and capability of self-diagnosis for individuals. Currently, according to the market’s need for appropriate remedies, more sensitive and selective devices are demanded. In that sense, paper-based diagnostic and analytical devices have attracted significant interest due to their low-cost, portability, simplicity and suitability of use in the field and developing countries. Here, the electrochemical sensing method was selected because of its agreement with markets’ need for paper-based analytical devices such as the ability of quantitative analysis, high sensitivity, fast sensor response and portability. Acetaminophen (N-acetyl-p-aminophenol), known as paracetamol, is an antipyretic analgesic, commonly used for the relief of headaches, backache, arthritis and other incidental pains and fevers. When taken in therapeutic doses, acetaminophen is safe, non-carcinogenic and does not have the secondary effects of acetylsalicylic acid. Surprisingly, acetaminophen is also the most common cause of poisoning worldwide. Acetaminophen poisoning can be the result of a single overdose ingestion (usually as an attempt at self-harm) or ingestion of excessive repeated doses or too-frequent doses, with therapeutic intent. Although the normal concentration range of acetaminophen for therapeutic purposes may vary due to personal constitution and physique, the plasma concentration of acetaminophen in humans follows a standard drug dose ranging from 50 to 100 μM. Therefore, a simple and quick measurement of acetaminophen doses is necessary for a continuous or urgent diagnosis. In the present study, we constructed a functional paper fluidic device and evaluated its electrochemical performance by analyzing acetaminophen in the presence of ascorbic acid. The device was composed of a single-walled carbon nanotube (SWCNT) electrode and nafion-modified nitrocellulose membrane. Negatively-charged nafion was employed to build up a more negative charge on the nitrocellulose membrane, and gold nanoparticles and polyglutamic acid (AuNP-PGA) were deposited on the SWCNT electrode to enhance the electrochemical performance of the device. The device had a vertical flow format in which the sample solution flowed vertically through the paper. Using the nafion-modified nitrocellulose membrane and AuNP-PGA/SWCNT film electrode as a component of the paper fluidic device, we obtained a distinguishable acetaminophen oxidation peak which was distinct from the ascorbic acid oxidation peak. The acetaminophen oxidation peak had a linear response with acetaminophen concentration, varying from 50 μM to 300 μM (r2 = 0.992), which was broader than the standard drug dose range. The device exhibited a sensitivity of 13.3 mA/M and a detection limit of 15.0 μM. The device was stable with a relative standard deviation of 3.3% (up to 2 weeks), and the reproducibility was 1.2 to 5.2%. Furthermore, the fabricated device accurately measured the amount of acetaminophen in pharmaceutical samples. From the results, we believe that the fabricated device is a promising electrochemical platform for the accurate and reproducible detection of acetaminophen and paper fluidic devices have the potential for simultaneous detection of multiple analytes with high selectivity by applying various materials such as enzymes, polymers, or aptamers on the membrane.

Effect of Acetaminophen Ingestion on Thermoregulation of Normothermic, Non-febrile Humans.

In non-febrile mouse models, high dose acetaminophen administration causes profound hypothermia. However, this potentially hazardous side-effect has not been confirmed in non-febrile humans. Thus, we sought to ascertain whether an acute therapeutic dose (20 mg⋅kg lean body mass) of acetaminophen would reduce non-febrile human core temperature in a sub-neutral environment. Ten apparently healthy (normal core temperature, no musculoskeletal injury, no evidence of acute illness) Caucasian males participated in a preliminary study (Study 1) to determine plasma acetaminophen concentration following oral ingestion of 20 mg⋅kg lean body mass acetaminophen. Plasma samples (every 20 min up to 2-hours post ingestion) were analyzed via enzyme linked immunosorbent assay. Thirteen (eight recruited from Study 1) apparently healthy Caucasian males participated in Study 2, and were passively exposed to 20°C, 40% r.h. for 120 min on two occasions in a randomized, repeated measures, crossover design. In a double blind manner, participants ingested acetaminophen (20 mg⋅kg lean body mass) or a placebo (dextrose) immediately prior to entering the environmental chamber. Rectal temperature, skin temperature, heart rate, and thermal sensation were monitored continuously and recorded every 10 min. In Study 1, the peak concentration of acetaminophen (14 ± 4 μg/ml) in plasma arose between 80 and 100 min following oral ingestion. In Study 2, acetaminophen ingestion reduced the core temperature of all participants, whereas there was no significant change in core temperature over time in the placebo trial. Mean core temperature was significantly lower in the acetaminophen trial compared with that of a placebo (p < 0.05). The peak reduction in core temperature in the acetaminophen trial was reached at 120 min in six of the thirteen participants, and ranged from 0.1 to 0.39°C (average peak reduction from baseline = 0.19 ± 0.09°C). There was no significant difference in skin temperature, heart rate, or thermal sensation between the acetaminophen and placebo trials (p > 0.05). The results indicate oral acetaminophen reduces core temperature of humans exposed to an environment beneath the thermal neutral zone. These results suggest that acetaminophen may inhibit the thermogenic mechanisms required to regulate core temperature during exposure to sub-neutral environments.

Pharmacokinetics and pharmacodynamics of oral acetaminophen in combination with codeine in healthy Greyhound dogs.

The purpose of this study was to determine the pharmacokinetic and antinociceptive effects of an acetaminophen/codeine combination administered orally to six healthy greyhounds. Antinociception was assessed using an electronic von Frey (vF) device as a mechanical/pressure model. Acetaminophen was administered at a dose of 600mg (14.4-23.1mg/kg) and codeine phosphate at 90mg (2.1-3.3mg/kg) equivalent to 67.5mg codeine base (1.6-2.5mg/kg). The geometric mean maximum plasma concentrations of acetaminophen, codeine, and codeine-6-glucuronide were 7.95μg/mL, 11.0ng/mL, and 3819ng/mL, respectively. Morphine concentrations were <1ng/mL. The terminal half-lives of acetaminophen, codeine, and codeine-6-glucuronide were 0.94, 1.71, and 3.12h. There were no significant changes in vF thresholds, except at 12h which decreased on average by 17% compared to baseline. The decrease in vF thresholds at 12h could be due to aversion, hyperalgesia, or random variability. The lack of antinociception in this study could be due to a true lack of antinociception, lack of model sensitivity, or specificity. Further studies using different models (including clinical trials), different dog breeds, multiple dose regimens, and a range of dosages are needed prior to recommended use or concluding lack of efficacy for oral acetaminophen/codeine in dogs.

Metabolism of AM404 From Acetaminophen at Human Therapeutic Dosages in the Rat Brain.

Background:Acetaminophen, an analgesic and antipyretic drug, has been used clinically for more than a century. Previous studies showed that acetaminophen undergoes metabolic transformations to form an analgesic compound, N-(4-hydroxyphenyl) arachidonamide (AM404), in the rodent brain. However, these studies were performed with higher concentrations of acetaminophen than are used in humans.Objectives:The aim of the present study was to examine the metabolism of AM404 from acetaminophen in the rat brain at a concentration of 20 mg/kg, which is used in therapeutic practice in humans, and to compare the pharmacokinetics between them.Materials and Methods:We used rat brains to investigate the metabolism of AM404 from acetaminophen at concentrations (20 mg/kg) used in humans. In addition, we determined the mean pharmacokinetic parameters for acetaminophen and its metabolites, including AM404.Results:The maximum plasma concentrations of acetaminophen and AM404 in the rat brain were 15.8 µg/g and 150 pg/g, respectively, with corresponding AUC0-2h values of 8.96 μg hour/g and 117 pg hour/g. The tmax for both acetaminophen and AM404 was 0.25 hour.Conclusions:These data suggest that AM404’s concentration-time profile in the brain is similar to those of acetaminophen and its other metabolites. Measurement of blood acetaminophen concentration seems to reflect the concentration of the prospective bioactive substance, AM404.

Pharmacokinetic Herb-Drug Interaction between Essential Oil of Aniseed (Pimpinella anisum L., Apiaceae) and Acetaminophen and Caffeine: A Potential Risk for Clinical Practice.

Aniseed (Pimpinella anisum L., Apiaceae) and its essential oil (EO) have been widely used. Because there are some data about the impact of aniseed EO on drug effects, this survey aimed to assess the potential of pharmacokinetic herb-drug interaction between aniseed EO and acetaminophen and caffeine in mice. The chemical analysis (gas chromatography-mass spectrometry) of aniseed EO has confirmed trans-anethole (87.96%) as the main component. The pharmacokinetic studies of intraperitoneally (i.p.) and orally applied acetaminophen (200 mg/kg) and caffeine (20 mg/kg) were performed in mice after 5 days of oral treatment with human equivalent dose of aniseed EO (0.3 mg/kg/day). The analysis of pharmacokinetic data showed that in the group treated by aniseed EO, the significant decrease in the peak plasma concentration of acetaminophen after oral application (p = 0.024) was revealed when compared with control group and the reduction of systemic exposure to the drug after oral application (74 ± 32% vs. 85 ± 35% in the control) was noted. The bioavailability of orally applied caffeine was also significantly decreased (p = 0.022) after the EO treatment in comparison with the control (57 ± 24% vs. 101 ± 29%). Therefore, the compromised therapeutic efficacy of acetaminophen and caffeine during the usage of aniseed EO preparations should be considered.

Effects of Ziziphus jujuba fruit extracts on cytochrome P450 (CYP1A2) activity in rats

Drug-drug interactions have become a serious problem in the clinic, since plant-based medicines are extensively used. The present study investigated the effects of Ziziphus jujuba fruit (ZJ) extract on the pharmacokinetics of phenacetin, a typical substrate of a cytochrome P450 enzyme CYP 1A2, in rats. The rats were pretreated with the water extract (1.0 g·kg−1) or the ethanolic extract (3.6 g·kg−1) of ZJ for 10 days, and the pharmacokinetics of phenacetin was investigated after intravenous administration. In an in vitro assay, acetaminophen formation in the hepatic microsomes of ZJ-treated rats was investigated to assess CYP1A2 activity. Our results demonstrated that the treatment with the water and ethanolic extracts of ZJ decreased the plasma concentration of phenacetin and increased the plasma concentration of acetaminophen, resulting in a 43.2% and 15.5% reduction in the AUC0–120 of phenacetin, respectively, and a 53.2% and 64.9% increase in the AUC0–120 of acetaminophen, respectively after intravenous administration. The water or ethanolic extract of ZJ significantly increased the clearance of phenacetin and acetaminophen formation in hepatic microsomes. In conclusion, ZJ extracts displayed effects on the pharmacokinetics of phenacetin and increased the CYP1A2 activity in rats. Therefore, precaution on drug-drug interactions should be taken when ZJ is co-administered with drugs metabolized by CYP1A2, which may result in decreased concentrations of these drugs.

Gastric Clearance Does Not Influence Glycemic Response to Cranberry Juice in Metabolic Syndrome Subjects.

Acetaminophen (AC) may be used to estimate gastric clearance effects on glycemic response to a dietary challenge. Healthy (n=6) and metabolic syndrome (MSD) subjects (n=14; BMI &gt;30) consumed reduced calorie cranberry juice (RCCBJ) (74 Cal/240 ml) or standard cranberry juice (CBJ) (110 Cal/240 ml) in single crossover fashion with 1 g AC. AC plasma concentration was measured pre‐challenge (0‐min) and 30, 60 and 120 min post‐prandially with HPLC. Plasma AC in healthy subjects after RCCBJ at 0, 30, 60 and 120 min was 0.14±0.20, 3.52±3.14, 16.07±8.54, 18.37±6.11 μg/ml. Plasma AC in healthy subjects after CBJ at 0, 30, 60 and 120 min was 0.33±0.37, 3.54±4.79, 19.80±15.03, 15.53±5.40 μg/ml. Plasma AC in MSD subjects after RCCBJ at 0, 30, 60 and 120 min was 0.11±0.25, 4.36±4.75, 10.64±6.60, 10.75±6.70 μg/ml. Plasma AC in MSD subjects after CBJ at 0, 30, 60 and 120 min was 0.16±0.28, 5.08±7.15, 12.86±10.15, 10.94±6.92 μg/ml. AC area under the curve (μg/ml·min) for healthy and MSD subjects to RCCBJ were 1382±523 and 934±569 respectively. AC area under the curve (μg/ml·min) for healthy and MSD subjects to CBJ were 1468±891 and 1062±644 respectively. No statistically significant differences in clearance were observed between RCCBJ and CBJ in either population, therefore in studies of cranberry juice glycemic response, gastric clearance is probably not a factor.