Plasma Ibuprofen Concentrations Research Articles

Controlled release ibuprofen-poloxamer gel for epidural use – A pharmacokinetic study using microdialysis in pigs

In order to avoid the risks of sideeffects of epidural local anesthetics and opioids, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) epidurally would be an interesting option of analgesic therapy. The fairly short duration of action of spinally administered NSAIDs, e.g., ibuprofen, may be prolonged by using controlled release poloxamer gel formulation. Using a microdialysis technique we studied the epidural and intrathecal pharmacokinetics of ibuprofen after its epidural administration as a poloxamer 407 formulation or a solution formulation. In addition, plasma ibuprofen concentrations were analyzed from central venous blood samples. Ibuprofen concentrations in the epidural space were significantly higher and longer lasting after the epidural gel injection compared with the epidural solution injection. The epidural AUC of ibuprofen was over threefold greater after epidural ibuprofen gel injection compared with the ibuprofen solution injection (p<0.001). The systemic absorption of ibuprofen from 25% poloxamer 407 gel was very low. The in situ forming poloxamer gel acted as a reservoir allowing targeted ibuprofen release at the epidural injection site and restricted ibuprofen molecules to a smaller spinal area. Ibuprofen diffusion from the epidural space to the intrathecal space was steady and prolonged. These results demonstrate that the use of epidurally injectable poloxamer gel can increase and prolong ibuprofen delivery from epidural space to the CSF enhancing thus ibuprofen entry into the central neuroaxis for spinal analgesia. Further toxicological and dose-finding studies are justified.

Testing the “read-across hypothesis” by investigating the effects of ibuprofen on fish

Human pharmaceuticals present in the environment have the potential to cause adverse effects on non-target organisms. The “read-across hypothesis” stipulates that pharmaceuticals will exhibit similar biological effects across species (e.g. human and fish) if the molecular target has been conserved and the effective drug concentrations are reached (Cmax). We tested this hypothesis by evaluating if ibuprofen, a non-selective inhibitor of prostaglandins and the cyclooxygenase (COX) enzyme, can mimic its primary effect in humans, on fish, at comparable plasma concentrations. The endpoints, prostaglandin E metabolite (PGEM) levels and the mRNA expression of COX (ptgs) gene, were measured in the gills of control and exposed fathead minnows (Pimephales promelas), using enzyme-immunoassay and quantitative real-time PCR (qPCR). Fish were exposed, for 24–72 h, to measured water concentrations of 9 (n = 12), 370 (n = 40) and 470 μg ibuprofen/L (n = 12). Water and blood plasma concentrations were determined using LC-MS/MS. Results showed that PGEM levels in fish exposed to 370 and 470 μg ibuprofen/L were significantly decreased compared to control fish, when mean plasma ibuprofen concentrations were 1.8–5.6-fold below the Cmax. The plasma ibuprofen concentrations and PGEM levels varied greatly between individuals. In fish exposed to 9 μg ibuprofen/L, when the mean plasma ibuprofen concentration was 224-fold below Cmax, no change in PGEM levels was observed. These data provide evidence for the read-across hypothesis, but suggest establishing a direct dose-response between internal plasma and PGEM is difficult, and would require significantly larger numbers of fish to overcome the inter-individual variation.

Usefulness of the chaotropic effect in sample preparation for chromatographic analysis of acidic xenobiotics in human plasma

In this study a new RP-HPLC with photo-diode array detection method for the determination of ibuprofen ((RS)-2-(4-isobutylphenyl)propionic acid) in human plasma samples was developed. Samples were prepared by SPE and analyzed by an isocratic elution mode over a C18 column using 80% methanol. A novel sample pretreatment method, based on the addition of ionic liquids possessing chaotropic ions to small human plasma sample (100 μL), was elaborated. 1-Butyl-3-methylimidazolium chloride and 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM BF4 ) were tested from the point of view of extraction yield. Quantification was based on calibration curve applying diclofenac as the internal standard. Owing to dilution of plasma sample by 2 mM aqueous solution of BMIM BF4 before SPE, appropriate sample purification and extraction yields higher than 95% with precision lower than 2% can be achieved. Linear coefficients of correlation (r(2)) were >0.99 in the range of 0.3-5 μg/mL ibuprofen concentration in plasma. The limit of quantification was 65 ng/mL and the detection limit for ibuprofen was 19.5 ng/mL.

Characteristics and Clinical Implications of the Pharmacokinetic Profile of Ibuprofen in Patients with Knee Osteoarthritis

Ibuprofen is a non-selective cyclo-oxygenase (COX)-1/COX-2 inhibitor used to treat pain conditions and inflammation. Limited data have been published concerning the pharmacokinetic profile and clinical effects of ibuprofen in patients with osteoarthritis (OA). In this paper we compared the pharmacokinetic and clinical profile of ibuprofen (at a dosage of from 800mg/day to 1800mg/day) administered in patients affected by severe knee OA. Ibuprofen was administered for 7days to patients who were scheduled to undergo knee arthroplasty due to OA. After 7days, the ibuprofen concentration in plasma and synovial fluid was measured through both high-performance liquid chromatography (HPLC)-UV and gas chromatography-mass spectroscopy (GC/MS), while clinical effects were evaluated through both visual analogue scale (VAS) and Western Ontario and McMaster Universities (WOMAC) scores. The Naranjo scale and the WHO causality assessment scale were used for estimating the probability of adverse drug reactions (ADRs). The severity of ADRs was assessed by the modified Hartwig and Siegel scale. Ibuprofen showed a dose-dependent diffusion in both plasma and synovial fluid, which was related to the reduction of pain intensity and improvement of health status, without the development of ADRs. Ibuprofen at higher dosages can be expected to provide better control of OA symptoms as a result of higher tissue distribution.

The effect of operational stressors on ibuprofen pharmacokinetics

To determine whether two of the major operational stressors associated with military missions in Afghanistan: dry heat and long durations of soldier patrol (SP), alter the pharmacokinetics of ibuprofen. Thirteen healthy and physically fit participants (19-32 years) were randomized to a four-arm crossover study, as follows: Arm 4 consisted of a simulated 2.5 h SP on a treadmill set at 4.5 km/h, 2% incline (15-min walk/5-min rest cycle) in a climatic chamber set to 42°C, 9% relative humidity. Arm 3 was similar to arm 4 but at room temperature, and arms 1 and 2 were sham SP to 3 and 4, respectively. For the final 2.5 h, participants remained in a semi-supine position. Each participant orally administered one 400-mg Advil Liqui-Gel® capsule. Blood samples were drawn over time and analyzed for (R)-ibuprofen and (S)-plasma ibuprofen concentrations using UPLC/MS/MS. Concentration-time data were analyzed by compartmental methods. Exercise significantly decreased the t(1/2abs) (h) of (S)-ibuprofen (0.26 to 0.17; p = 0.015) and T(max) (h) for both (R)-ibuprofen (0.97 to 0.73; p = 0.008) and (S)-ibuprofen (1.13 to 0.84; p = 0.005). Values for t(lag) (h) also decreased with exercise for both (R)-ibuprofen (0.38 to 0.22; p = 0.005), and (S)-ibuprofen (0.39 to 0.23; p = 0.001). Exercise stress had a significant impact on the absorption profile of (R)- and (S)-ibuprofen. Excessive self-administration rate and dose may not be due to the military operational stressors of heat and soldier presence patrol.

Pharmacokinetics, safety, and tolerability of a rapid infusion of i.v. ibuprofen in healthy adults

The pharmacokinetics, safety, and tolerability of a rapid infusion of i.v. ibuprofen in healthy adults were evaluated. Methods In this randomized, double-blind, placebo-controlled, single-dose, crossover study, 12 healthy subjects age 18-65 years were randomized to receive a single dose of either 800 mg i.v. ibuprofen (infused over five to seven minutes) concomitantly with an oral placebo or 800 mg oral ibuprofen with concomitant i.v. placebo (0.9% sodium chloride injection). After a six-day washout period, subjects received the treatment not previously received. Blood samples were taken 1 hour before each dose of study medication was administered and throughout the 12 hours thereafter. Plasma ibuprofen concentrations were determined using validated liquid chromatography-tandem mass spectrometry methods. The frequency and severity of treatment-emergent adverse effects were monitored throughout the study. The maximum plasma concentration (C(max)) of i.v. ibuprofen was approximately twice that of oral ibuprofen, and the (t(max)) of i.v. ibuprofen was 0.11 hour, compared with 1.5 hours for oral ibuprofen. However, the elimination half-life of i.v. and oral ibuprofen did not differ, both of which were approximately 2 hours. Oral ibuprofen was 100% bioavailable; therefore, the area under the concentration-time curve did not differ between i.v. and oral ibuprofen. In addition, i.v. ibuprofen infused over five to seven minutes did not differ in terms of safety or tolerability when compared with oral ibuprofen. I.V. ibuprofen, when administered over five to seven minutes in healthy subjects, achieved a higher C(max) and a more-rapid t(max) than did oral ibuprofen and was found to be safe and well tolerated.

Characterization of organogel as a novel oral controlled release formulation for lipophilic compounds

A low molecular mass gelator can form soft solids in a variety of organic liquids and vegetable oils. These soft solids are generally called organogels. In this study, we prepared organogel using 12-hydroxystearic acid (12-HSA) as a gelator for soybean oil and investigated its characteristics as a controlled release formulation for lipophilic compounds. The release rate of ibuprofen, a model lipophilic compound, from organogel decreased with the increase of 12-HSA concentration in the formulation; however, the difference in the concentration of 12-HSA in the formulation did not affect the diffusivity of ibuprofen in the organogel. The erosion constant of organogel in the intestinal tract was examined by using simulated gastric fluid and intestinal fluid. Regardless of 12-HSA concentration in the formulation, organogel is very stable in the simulated gastric fluid. On the other hand, the erosion constant of organogel in the simulated intestinal fluid increased with the decreasing concentration of 12-HSA. Therefore, it is speculated that the difference in the release rate of ibuprofen among organogels with various concentrations of 12-HSA was mainly caused by the difference in the erosion rate. To characterize the organogel effect in vivo, ibuprofen was orally administered to rats in an aqueous suspension or organogel. Ibuprofen concentration in plasma rapidly increased after administration with an aqueous suspension, whereas organogel suppressed the rapid absorption. In conclusion, organogel is clearly useful as an oral controlled release formulation for lipophilic compounds.

Comparative bioavailability of three ibuprofen formulations in healthy human volunteers

To assess the bioequivalence of three ibuprofen formulations (Test formulation: ibuprofen (400 mg capsule) manufactured by Cardinal Health Brasil 402 Ltda. (Sorocaba, Brazil) and licensed to Boehringer Ingelheim do Brasil Quim. e Farm. Ltda. (SA poundo Paulo, Brazil); Reference formulation (1): ibuprofen (AdvilA(R); 2 A 200 mg coated tablet) from Wyeth-Whitehall Ltda. (Itapevi, Brazil); Reference formulation (2): ibuprofen (AliviumA; 8 ml A 50 mg/ml solution) from Schering Plough S.A. (Rio de Janeiro, Brazil)) in 24 healthy volunteers of both sexes. The study was conducted using an open, randomized, three-period crossover design with at least 5-day washout interval. Plasma samples were obtained over a 24-h period. Plasma ibuprofen concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) with negative ion electrospray ionization using multiple reaction monitoring (MRM). The following pharmacokinetic parameters were obtained from the ibuprofen plasma concentration vs. time curves: AUC(last), AUC(trunctmax), AUC(inf) and C(max). The limit of quantification for ibuprofen was 0.1 microg A ml(1). The geometric mean with corresponding 90% confidence interval (CI) for Test/Reference (1) percent ratios were 114.24% (90% CI = 105.67, 123.50%) for C(max), 98.97% (90% CI = 94.69, 103.44%) for AUC(last) and 99.40% (90% CI = 95.21, 103.78%) for AUC(inf). The geometric mean and respective 90% confidence interval (CI) for Test/Reference (2) percent ratios were 108.38% (90% CI = 100.19, 117.25%) for C(max), 100.79% (90% CI = 96.39, 105.40%) for AUC(last) and 101.26% (90% CI = 96.94, 105.77%) for AUC(inf); t(max) for the 400 mg Test capsule was shorter than that for the 2 A 200 mg Reference (1) tablets (p < 0.002). Since the 90% CI for AUC(last), AUC(inf) and Cmax ratios were within the 80 - 125% interval proposed by the US FDA, it was concluded that ibuprofen formulation manufactured by Cardinal Health Brasil 402 Ltda. and licensed to Boehringer Ingelheim do Brasil Quim. e Farm. Ltda. is bioequivalent to the AdvilA and AliviumA formulations with regard to both the rate and the extent of absorption.

Effects of St. John's Wort Supplementation on Ibuprofen Pharmacokinetics

St. John's wort is a popular herbal supplement that has been involved in various herb-drug interactions. Experimental findings suggest that the supplement may impact CYP2C9 metabolism. CYP2C9 is responsible for the irreversible metabolism of ibuprofen. To examine the effect of 3 weeks of St. John's wort administration on the stereoselective pharmacokinetics of ibuprofen. Eight male subjects participated in this study. The single-dose pharmacokinetics of ibuprofen were evaluated before and after 21 days of St. John's wort administration. Plasma ibuprofen concentrations were determined, using a stereoselective, reversed-phase HPLC assay. Model independent methods were used to evaluate the pharmacokinetics of each ibuprofen enantiomer. Data were analyzed by 2 way ANOVA testing and confidence interval testing. S(+)-ibuprofen mean +/- SD AUC and maximum concentration (C(max)) values were 131.6 +/- 26.8 microg x h/mL and 31.8 +/- 7.33 microg/mL, respectively, for control samples and 122.4 +/- 32.9 microg x h/mL and 33.6 +/- 7.83 microg/mL, respectively, after St. John's wort treatment. R(-)-ibuprofen mean AUC and C(max) values were 85.1 +/- 26.6 microg x h/mL and 28.4 +/- 8.72 microg/mL, respectively, for control samples and 87.7 +/- 30.1 microg x h/mL and 30.0 +/- 8.97 microg/mL, respectively, for St. John's wort treatment samples. St. John's wort administration resulted in no significant effects on the C(max) and AUC of either stereoisomer. A 31% decrease in S(+)-ibuprofen mean residence time (p = 0.02) was observed. St. John's wort administration for 21 days had no apparent clinically important impact on the single-dose pharmacokinetic parameters of S(+)- and R(-)-ibuprofen. Although St. John's wort treatment appears to significantly reduce the mean residence time of S-ibuprofen, no ibuprofen dose adjustments appear warranted when the drug is administered orally with St. John's wort, due to the lack of significant change observed in ibuprofen AUC and C(max) for either enantiomer.

The relationship between plasma ibuprofen concentrations and toxicity in acute ibuprofen overdose.

1. The information available from the literature and from a prospective survey of ibuprofen overdose being undertaken by the London centre of the National Poisons Information Service (NPIS) was examined utilizing the Generalized Linear Interactive Modelling (GLIM) statistical computing package. 2. This confirmed that timed ibuprofen plasma concentrations were related to the symptoms of tachycardia, dizziness, tinnitus, ocular symptoms and coma/stupor as well as to reversible renal impairment and plasma hepatic enzyme elevation. 3. The best model of the relationship between symptomatic toxicity and timed ibuprofen plasma concentrations, was an exponential equation in time. Because of the lack of specificity or sensitivity in this model, and absence of demonstrable clinical advantages from its application, we do not recommend its use as a guide to predict toxicity. 4. However analysis of a larger information base utilizing similar methodology could, by increasing the statistical power of the resultant model, provide a useful means of predicting ibuprofen toxicity. 5. A previously postulated relationship between post-ingestion ibuprofen plasma concentrations and toxicity was not confirmed.

Rapid high-performance liquid chromatographic assay for the simultaneous analysis of non-steroidal antiinflammatory drugs in plasma

A high-performance liquid chromatographic assay has been developed for the determination of a number of non-steroidal anti-inflammatory drugs in plasma. The samples were prepared by adding acetonitrile and perchloric acid to 200 μl of plasma. Diclofenac, fenoprofen, ketoprofen, naproxen, phenylbutazone, piroxicam and sulindac were quantified in the supernatant produced using a mobile phase of phosphoric acid 0.03% (pH 2.5) -acetonitrile and a detecting wavelength of 254 nm. The reproducibility, linearity, precision and specificity of the assay were determined and found to be satisfactory. Alteration of the detection wavelength to 229 nm also permitted accurate determination of ibuprofen concentration in plasma. While reduction of the organic solvent content of the mobile phase and alteration of wavelength to 313 nm produced a system capable of quantizing salicylate and its metabolites in plasma and by further reducing the detecting wavelength to 237 nm, aspirin also was quantifiable. These methods have been applied in a cross-sectional study of medication compliance among rheumatoid arthritis patients treated with non-steroidal anti-inflammatory drugs.

Acute poisoning with ibuprofen.

1 Seventy five cases of ibuprofen overdose were recorded during a two year survey. 2 Details of the symptoms, treatment and the eventual outcome are known for 64% of the cases. The majority of the patients had no symptoms or only mild symptoms such as nausea or vomiting. 3 In the three cases where more serious symptoms were reported, the role of ibuprofen was not certain. 4 Laboratory analyses available for 13 cases demonstrate that plasma ibuprofen concentrations of up to 704 mg/l could be associated with no symptoms. 5 The data suggest that ibuprofen is of low toxicity in acute overdose and that therapy used should be supportive only.