Bioavailability Of Paracetamol Research Articles

Overcoming the paracetamol dose challenge with wrinkled mesoporous carbon spheres

Paracetamol is the most commonly used antipyretic and analgesic drug in the world. The key challenge in paracetamol therapy is associated with the frequency of the dosing. Depending on the gastric filling within 10–20 min paracetamol is released and rapidly absorbed from the gastrointestinal tract. Therefore, it must be taken three or four times a day. To address the dose challenge it is desirable that the paracetamol release profile follows the zero-order kinetic model (constant rate of drug release per unit time). This goal can be achieved by using a suitable porous carrier system. Herein, non-toxic wrinkled mesoporous carbons with unique morphology were synthesized via the hard template method as new carriers for paracetamol. These particles can precisely modulate the release of paracetamol over 24 h in a simulated gastric fluid according to the zero-order kinetic model completely eliminating the initial burst release. Overall, these systems could significantly enhance the bioavailability of paracetamol and prolong its therapeutic effect in numerous diseases such as cold, flu, COVID-19, and severe pain.

Increased Paracetamol Bioavailability after Sleeve Gastrectomy: A Crossover Pre- vs. Post-Operative Clinical Trial.

Oral drug bioavailability may be significantly altered after laparoscopic sleeve gastrectomy (LSG), the most popular bariatric procedure worldwide. Paracetamol (acetaminophen) is the post-bariatric analgesic/antipyretic drug of choice. In this work we studied and analyzed the LSG effects on systemic bioavailability and pharmacokinetics of paracetamol after oral administration of solid vs. liquid dosage form. A 4-armed, pharmacokinetic, crossover trial was performed in patients enrolled for LSG. Single paracetamol dose (500 mg), as caplet (n = 7) or syrup (n = 5), was administered before vs. 4–6 months post-LSG. Bioavailability was enhanced after LSG; in the caplet groups, average AUC0–t increased from 9.1 to 18.6 µg·h/mL with AUC0–t difference of 9.5 µg·h/mL (95% CI 4.6–14.5, p = 0.003). Cmax increased from 1.8 (95% CI 1.2–2.5) to 4.2 µg/mL (3.6–4.8) after LSG (p = 0.032). In the syrup groups, AUC0–t increased from 13.4 to 25.6 µg·h/mL, with AUC0–t difference of 12.2 µg·h/mL (95% CI 0.9–23.5, p = 0.049). Cmax changed from 5.4 (95% CI 2.5–8.4) to 7.8 µg/mL (6.1–9.6), and systemic bioavailability was complete (102%) after the surgery. Overall, decreased paracetamol exposure in obesity, with recovery to normal drug levels (caplet) or even higher (syrup) post-LSG, was revealed. In conclusion, attention to paracetamol effectiveness/safety in obesity, and after bariatric surgery, is prudent.

Pharmacokinetics and Bioavailability of a Fixed-Dose Combination of Ibuprofen and Paracetamol after Intravenous and Oral Administration.

Background and ObjectivesPreviously published studies have suggested the lack of a pharmacokinetic interaction between ibuprofen and paracetamol when they are delivered as a fixed-dose oral combination. The aim of this study was to determine the pharmacokinetic profile and safety of a fixed-dose intravenous (IV) combination, containing 3 mg/mL ibuprofen and 10 mg/mL paracetamol, in comparison with its individual components. The study also assessed the relative bioavailability of the same doses of the active ingredients when they were administered as an oral formulation.MethodsA single-dose, open-label, randomized, five-period cross-over sequence pharmacokinetic study was undertaken in 30 healthy volunteers. Serial plasma samples were assayed for both paracetamol and ibuprofen concentrations, using validated liquid chromatography–tandem mass spectrometry methods. Pharmacokinetic parameters were computed using standard non-compartmental analyses. Adverse events were also assessed. The ratios of the maximum measured plasma concentration (Cmax), the area under the plasma concentration–time curve (AUC) from time zero to the time of the last measurable plasma concentration (AUCt) and AUC from time zero to infinity (AUC∞) were analysed for bioequivalence as determined by 90 % confidence intervals.ResultsThe pharmacokinetic parameters of ibuprofen and paracetamol were very similar for the combination and monotherapy IV preparations; the ratios of the Cmax, AUCt and AUC∞ values fell within the 80–125 % acceptable bioequivalence range. Precise dose proportionality for both compounds was also determined for the half dose of the IV formulation in comparison with the full dose. The relative bioavailability of paracetamol (93.78 %) and ibuprofen (96.45 %) confirmed the pharmacokinetic equivalence of the oral and IV formulations of the fixed-dose combination.ConclusionConcomitant administration of 3 mg/mL ibuprofen and 10 mg/mL paracetamol in a fixed-dose IV combination does not alter the pharmacokinetic profiles of either drug. The IV and oral dose forms of such a combination are pharmacokinetically equivalent.

Glucosamine Enhances Paracetamol Bioavailability by Reducing Its Metabolism

Paracetamol has an extensive first-pass metabolism that highly affects its bioavailability (BA); thus, dose may be repeated several times a day in order to have longer efficacy. However, hepatotoxicity may arise because of paracetamol metabolism. Therefore, this project aimed to increase paracetamol BA in rats by glucosamine (GlcN). At GlcN-paracetamol racemic mixture ratio of 4:1 and paracetamol dose of 10 mg/kg, paracetamol area under the curve (AUC) and maximum concentration (Cmax ) were significantly increased by 99% and 66%, respectively (p < 0.05). Furthermore, paracetamol AUC and Cmax levels were increased by 165% and 88% in rats prefed with GlcN for 2 days (p < 0.001). Moreover, GlcN significantly reduced phase Ι and phase I/ΙΙ metabolic reactions in liver homogenate by 48% and 54%, respectively. Furthermore, GlcN molecule was found to possess a good in silico binding mode into the CYP2E1 active site-forming bidentate hydrogen bonding with the Thr303 side chain. Finally, serum ALT and AST levels of rats-administered high doses of paracetamol were significantly reduced when rats were prefed with GlcN (p < 0.01). In conclusion, GlcN can increase the relative BA of paracetamol through reducing its metabolism. This phenomenon is associated with reduction in hepatocytes injury following ingestion of high doses of paracetamol.

Evidence of reduced oral bioavailability of paracetamol in rats following multiple ingestion of grapefruit juice.

The aim of the current investigation was to assess the ability GFJ to modulate the pharmacokinetic profile of paracetamol following single or repeated administrations of GFJ in Sprague-Dawley rats. Diclofenac and carbamazepine were both used as positive controls. Rats received single GFJ or single distilled water doses or pretreated with three doses of GFJ prior to test drug administration. Blood samples were collected, processed and analyzed using validated HPLC methods, and pharmacokinetic data were constructed for each group. Increase in the bioavailability of both diclofenac and carbamazepine following multiple GFJ ingestion was revealed. Conversely, the bioavailability of paracetamol was significantly reduced following multiple GFJ administration. The percentage of reduction in the C max and AUC of paracetamol were calculated as 31 and 51 %, respectively, compared to none-GFJ-treated control (P < 0.05). The T(max) was not essentially changed. In conclusion, frequent administration of GFJ was confirmed to modulate the pharmacokinetics of paracetamol in rats by reducing its bioavailability. Meanwhile, it may be advisable not to ingest large amounts of GFJ along with paracetamol to avoid a possible potential loss of the efficacy.

Corrigendum

The authors would like to bring attention to the error published in 'Bioavailability of paracetamol, phenylephrine hydrochloride and guaifenesin in a fixed-combination syrup versus an oral reference product' 'Annick Janin and Joelle Monnet' Journal of International Medical Research 42(2) pp. 347-359. DOI: 10.1177/0300060513503762.

Bioavailability of paracetamol, phenylephrine hydrochloride and guaifenesin in a fixed-combination syrup versus an oral reference product

The primary objective of this study was to compare the bioavailability of paracetamol, phenylephrine hydrochloride and guaifenesin in a new oral syrup with an established oral reference product. The secondary objective was to compare the safety of the new syrup and the reference product. This was a single-centre, open-label, randomized, reference-replicated, crossover study. Healthy adult volunteers received one dose of syrup and two separate doses of a reference oral liquid formulation in a randomized sequence over three study periods, with a washout interval of ≥ 7 days between study periods. Blood samples were taken regularly postdose and analysed for paracetamol, phenylephrine hydrochloride and guaifenesin concentrations; adverse events were recorded. This study enrolled 45 subjects. For paracetamol and guaifenesin, the syrup and reference product were considered to be bioequivalent. Bioequivalence was not shown for phenylephrine hydrochloride. All adverse events were mild or moderate, most of which were considered formulation related. The syrup did not reach bioequivalence with the reference product, as bioequivalence could not be shown for phenylephrine hydrochloride. This may be due to differences in the excipients between the two products. Both the syrup and the reference product had a good safety profile and were well tolerated.

The effect of the molecular weight of polyethylene glycol on the bioavailability of paracetamol-polyethylene glycol solid dispersions.

A controlled study of the bioavailability of paracetamol in solid dispersion with PEG 6000, 10000 and 20000 has been made. The total amount of paracetamol excreted in urine increased with molecular weight of the PEG, but the rate of absorption of the drug was unaffected.

Study of paracetamol 1g oral solution bioavailability

The aim of this work was to assess paracetamol bioavailability after administering 1 g in oral solution. Eighteen healthy volunteers were selected for this open-label study. A total of 15.4 ml of Gelocatil Oral Solution (Laboratorios Gelos, S.L.), corresponding to 1 g of paracetamol, were administered to fasting subjects. Blood samples were collected at 0 min, 10 min, 20 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h and 12 h. Paracetamol plasma concentrations were determined by reverse-phase high-performance liquid chromatography. The study was conducted without deviations from protocol. Pharmacokinetic data from 18 subjects were allowed for estimating fast and high-paracetamol bioavailability: t(max) 20 min (10-45) [median (range)], C(max) 24. 3 mg/l (6.5) [mean (standard deviation)], AUC(0-t) 64.0 mg h/l (16.1) and AUC(0-00) 68.1 mg h/l (17.9). These results are comparable to those described for Gelocatil Oral Solution given at a 650 mg dose and for immediate release Gelocatil 650 mg tablets. Absorption speed was very fast, similar to that described for other oral-solution formulations, which provides an immediate onset of pain and fever relief. The results of this study show suitable bioavailability for 1 g Gelocatil Oral Solution, with fast-absorption speed that provides an immediate onset of pain and fever relief.

Pharmacokinetic Interactions of Antihepatotoxic Wedelolactone with Paracetamol in Wistar Albino Rats

Eclipta alba. (Linn.) Hassk. (Asteraceae), popularly known as “bhringraj,” is effective against liver damage caused by various hepatotoxins and is used traditionally in Indian phytoformulations. For enhanced in vitro. production of wedelolactone (W), leaves of aseptically germinated seedlings were cultured on Murashige and Skoog's (MS) medium supplemented with plant growth regulators under controlled and standardized chemical and environmental conditions. The wedelolactone was extracted, isolated, purified, chemically characterized, and quantitatively estimated. Rats were divided into four groups of six animals each and given paracetamol (250 mg/kg, p.o.), paracetamol (250 mg/kg, p.o.) with wedelolactone (100 mg/kg, p.o.), paracetamol (250 mg/kg, p.o.) with plant leaves extract (250 mg/kg, p.o.), paracetamol (250 mg/kg, p.o.) with leaf callus extract (250 mg/kg, p.o.), respectively. Blood samples were collected at 1, 2, 3, 4, and 6 h after drug administration, and plasma paracetamol concentration was determined. Pharmacokinetic studies revealed that concomitant administration of wedelolactone with paracetamol does not affect the bioavailability of paracetamol. There was no change in Cmax between paracetamol and paracetamol with wedelolactone, but the Tmax of paracetamol was 2 h in control animals while administration of wedelolactone and extracts with paracetamol resulted in shifting of Tmax from 2 to 3 h without affecting the area under the curve (AUC). Because wedelolactone does not alter the bioavailability of paracetamol significantly and also shows a hepatoprotective effect, its use may be recommended in prolonged paracetamol therapy or paracetamol toxicity.

The Talinolol Double-Peak Phenomenon Is Likely Caused by Presystemic Processing After Uptake from Gut Lumen

Evaluation of the double-peak phenomenon during absorption of the beta(1)-selective blocker talinolol relative to paracetamol, which is well absorbed from all parts of the gut, and relative to vitamin A, which is absorbed via the lymphatic pathway. Talinolol was given with paracetamol and retinyl palmitate in fast-disintegrating, enteric-coated, and rectal soft capsules to 8 fasting male healthy subjects (21-29 years, 68-86 kg). To evaluate whether the talinolol double-peak is associated with processes of food absorption, a breakfast was served 1 h after administration of a fast disintegrating capsule. Bioavailability of talinolol in enteric-coated and rectal capsules was significantly reduced by about 50% and 80%, respectively, despite unchanged bioavailability of paracetamol. Double-peaks appeared after 2-3 h and 4-6 h with talinolol given as fast-liberating capsules. Food increased the maximum concentrations significantly (223 +/- 76 microg/ml vs. 315 +/- 122 microg/ml, p < 0.05) and shifted the second peak of talinolol to shorter t(max) values (3.8 +/- 1.2 h vs. 2.1 +/- 0.6 h, p < 0.05), which was associated with faster absorption of retinyl palmitate. Pharmacokinetic model fits showed that about half of the oral talinolol dose given with and without meal is drained from the intestine via a presystemic storage compartment. The double-peak phenomenon of talinolol is likely caused by a presystemic storage compartment, which represents the complex interplay of heterogeneous uptake and kick-back transport processes along the intestinal-hepatic absorption pathway.

Oral sustained delivery of paracetamol from in situ-gelling gellan and sodium alginate formulations

The purpose of this study was to evaluate the potential for the oral sustained delivery of paracetamol of two formulations with in situ gelling properties. Oral administration of aqueous solutions of either gellan gum (1.0%, w/v) or sodium alginate (1.5%, w/v) containing calcium ions in complexed form resulted in the formation of gel depots in rabbit and rat stomachs as a consequence of the release of the calcium ions in the acidic environment. In vitro studies demonstrated diffusion-controlled release of paracetamol from the gels over a period of 6 h. The bioavailability of paracetamol from the gels formed in situ in the stomachs of rabbits following oral administration of the liquid formulations was similar to that of a commercially available suspension containing an identical dose of paracetamol.

Modelling paracetamol urine metabolites

Introduction Glucuronidation is immature in neonates and sulphation is the dominant metabolic pathway (glucuronide/sulphate 0.34). Adult glucuronide/sulphate ratios (+2) are believed to occur at 12 years (1). Different UDP‐glucuronosyltransferases, the rate‐limiting enzyme in neonates, mature at different rates: that responsible for bilirubin metabolism, for example, within the first 3 months of life. These enzymes are regulated not only by ontogenic, but also by genetic processes. Paracetamol clearance approaches adult rates at 1 year, when standardised to an allometric 3/4 power model (2). Urinary metabolites in 11‐month‐old children were investigated to determine metabolic pathway predominance at this age for paracetamol.Methods Ethical committee approval was granted and informed consent from parents/caregivers was obtained for each study child. Children (n = 158) nursed in PICU after craniosyntosis surgery were given regular paracetamol (LD 40 mg/kg, MD 20 mg·kg−1 6–8 h over 24 h). Serial serum concentrations were measured in 150 children (3). Urine was collected at 3 h intervals for 24 h and assayed for paracetamol, paracetamol glucuronide and paracetamol sulphate in 15 children.Data were analysed using differential equations for a 7 compartment model with the first order conditional estimate method using ADVAN 6, Tol = 5 of NONMEM V. Data were pooled with another study (2) to characterise oral bioavailability.Results Children had a mean age 11.8 SD 2.6 months and weight 9.1 SD 1.9 kg. Oral paracetamol bioavailability was low compared to rectal. due to nasogastric loss and vomiting. Sulphate metabolite clearance was 2.85 l·h−1·70kg−1 while glueuronide metabolite clearance was 6.07 l·h−1·70kg−1. Unmetabolised paracetamol urinary clearance (3.65 l·h−1·70kg−1) was unexpectedly large and was related to urine production with an exponential function. We were unable to estimate other metabolite (e.g. mercaptopurine/cysteine metabolites from glutathione) clearances.Discussion The glucuronide/sulphate ratio of approximately 2 that is described in children aged 12 years (1) was reached by the age of 1 year. Earlier reports suggested that this ratio be attained slowly during childhood. Our data suggests that maturation of the glucuronide system for paracetamol is more rapid during the first year than previously assumed.

Oral Paracetamol Bioavailability in Rats Subjected to Experimental Spinal Cord Injury

The purpose of the present study was to examine the time dependence of oral paracetamol (acetaminophen) bioavailability in an experimental model of spinal cord injury (SCI). Female Sprague-Dawley rats were subjected to spinal cord contusion at the T8-T9 level by the weight drop method producing permanent paraplegia. Oral paracetamol bioavailability after administration of a single 100 mgkg-1 dose was determined 1, 12, and 50 d after SCI. Cmax and AUC were significantly decreased 1 d after SCI compared to sham-injured controls. This reduction, however, was temporary, as there was a recovery of bioavailability parameters which was partial 12 d after SCI, being complete by day 50. The present results confirm the usefulness of animal models for the characterization of the effect of SCI in drug kinetics. Data show that SCI induces significant changes in paracetamol pharmacokinetics. Nonetheless, despite the fact of a permanent loss of functions related to locomotion, pharmacokinetic alterations evolved with time.

Oral Paracetamol Bioavailability in Rats Subjected to Experimental Spinal Cord Injury

The purpose of the present study was to examine the time dependence of oral paracetamol (acetaminophen) bioavailability in an experimental model of spinal cord injury (SCI). Female Sprague–Dawley rats were subjected to spinal cord contusion at the T8–T9 level by the weight drop method producing permanent paraplegia. Oral paracetamol bioavailability after administration of a single 100 mg kg−1 dose was determined 1, 12, and 50 d after SCI. Cmax and AUC were significantly decreased 1 d after SCI compared to sham-injured controls. This reduction, however, was temporary, as there was a recovery of bioavailability parameters which was partial 12 d after SCI, being complete by day 50. The present results confirm the usefulness of animal models for the characterization of the effect of SCI in drug kinetics. Data show that SCI induces significant changes in paracetamol pharmacokinetics. Nonetheless, despite the fact of a permanent loss of functions related to locomotion, pharmacokinetic alterations evolved with time. © 1997 John Wiley & Sons, Ltd.

A Validated High-Performance Liquid Chromatographic Method for the Determination Of Paracetamol and Its Major Metabolites in Urine

Abstract A reversed-phase high-performance liquid chromatographic (RP-HPLC) method employing UV-detection (248 nm), 5 μm Resolve C18 as stationary phase (in a 8 × 100 mm Waters Radial-Pak cartridge) and 0.1 M potassium phosphate monobasic/methanol/glacial acetic acid (95:4:1, v/v/v) as mobile phase was developed for the rapid and simultaneous determination of paracetamol and its major metabolites (its glucuronide and sulphate conjugates) in urine. The method requires only minimal sample preparation and chromatographic run time is only 6 min. For determination of paracetamol, the precision (inter-assay RSD ranged from 1.60–0.66% between 5 and 100 μg mL−1) and limits of detection (2 ng mL−1) were satisfactory, as were these parameters for determination of the major metabolites. In the course of studies on paracetamol bioavailability and metabolism, over 1500 samples have been assayed using this method. Herein we report its use for monitoring of the levels of paracetamol and its major metabolites in the urine of fifteen normal healthy volunteers given a single oral dose of 500 mg.

An Experimental Model for the Study of Pharmacokinetic Alterations Induced by Spinal Cord Injury in the Rat

The purpose of this work was to provide an experimental model for the study of pharmacokinetic alterations induced by spinal cord injury in male and female Wistar rats. Animals were submitted to spinal cord contusion at the T8–T9 level by the weight drop method. A single oral paracetamol dose (100 mg kg−1) was administered 24 h after injury and blood samples were drawn for a period of 240 min. Paracetamol concentration in whole blood was determined and pharmacokinetic parameters were estimated. Cmax and AUC were significantly lower in injured animals, compared with sham-lesioned controls, while differences in tmax and t1/2 did not reach statistical significance. Changes in oral paracetamol kinetics induced by spinal cord injury followed a similar pattern in males and females. It is concluded that oral paracetamol bioavailability is importantly reduced by spinal cord injury. The contusion procedure here described appears to be an adequate model for the characterization of pharmacokinetic alterations.

Influence of amount of hard fat in suppositories on the in vitro release rate and bioavailability of paracetamol II. A comparison between three compositions and a rectal solution

The flow-through cell has been used to investigate whether it is possible to discover any relationship between the in vitro dissolution rate of paracetamol from suppositories and the plasma concentrations reached after administration to eight healthy volunteers. A rectal solution was used as a reference. Three suppository compositions were varied with regard to amount of drug substance in relation to total suppository weight and size. The in vivo study was designed to explore the use of statistical moment analysis and convolution/deconvolution in the association of in vivo data and in vitro dissolution results. An increase in both rate and extent of bioavailability was observed when decreasing the fraction and increasing the size, but it was not explained to what degree each of these factors contributed. The flow-through method using a 22.6 mm cell, primarily developed for oral dosage forms, was found to produce dissolution profiles which associated well with the plasma concentration profiles obtained both when a statistical moment analysis and the convolution method was applied. The most optimal flow rate studied was 28 ml/min which reflected the in vivo situation better than a lower or a higher flow rate.

Influence of amount of hard fat in suppositories on the in vitro release rate and bioavailability of paracetamol and codeine. I. A comparison of three suppository compositions in vivo

The flow-through cell at a flow rate of 16 and 8 ml/min has been used to investigate how the amount of paracetamol and codeine phosphate, in relation to the total weight of a lipophilic suppository, influences the in vitro dissolution rate. Two in vivo studies explored how the rate and extent of bioavailability in humans varied as a function of fraction of drug substances. Despite an approx. 20-fold difference in aqueous solubility between paracetamol and codeine phosphate, the lipophilicity controlled the in vitro release and bioavailability. Decreasing the amount of paracetamol and codeine phosphate in relation to total suppository weight and increasing the size of the suppository resulted in a faster absorption rate and an increased extent of bioavailability. This was more pronounced for paracetamol. The flow-through cell was found to produce dissolution profiles which were in agreement with the plasma concentration profiles obtained, indicating that the lower flow rate reflected the in vivo situation more correctly than the higher flow rate. The intra-individual variation when administering one composition on two different occasions was found to be relatively small for five of the subjects who participated in both studies.

Absorption of paracetamol from suppositories in geriatric patients with fecal accumulation in the rectum

The bioavailability of paracetamol from suppositories was studied in 16 geriatric in-patients in stable clinical condition; 9 had significant amounts of feces in the rectum. Rectal accumulation of feces reduced the peak plasma paracetamol concentration by 32% (p = 0.05) and the AUC0-8h by 27% (p = 0.04). The peak concentration, however, appeared earlier among patients with rectal accumulation of feces. Compared to findings in 6 healthy young controls, geriatric patients had higher plasma concentrations of the main paracetamol metabolites.