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At least 19 recordsLinked to original sources
PubMed1995

Efficacy of topical flurbiprofen and indomethacin in preventing pseudophakic cystoid macular edema. Flurbiprofen-CME Study Group I.

We evaluated two topical cyclo-oxygenase inhibitors (COIs), 0.03% flurbiprofen and 1% indomethacin, for their ability to prevent pseudophakic cystoid macular edema (CME). The study was a randomized, double-masked, vehicle-controlled, parallel group, clinical trial for six months at eight sites in Canada and two in Germany. The study population consisted of 681 patients who had extracapsular cataract extraction and posterior chamber lens implantation. Flurbiprofen, indomethacin, or the vehicle was instilled into the eye four times daily for two days preoperatively and three months postoperatively. Results were measured by angiographic and clinical CME at visit 5 (day 21-60) and visit 7 (day 121-240) and by contrast sensitivity and Snellen visual acuity at all five postoperative visits. At visit 5, the incidence of angiographic CME was comparable in the two COI treatment groups (16.8% flurbiprofen, 12.4% indomethacin) and was significantly lower than in the vehicle group (32.2%). The incidence of clinical CME was also significantly lower in the COI-treated groups (10.7% flurbiprofen, 9.6% indomethacin) than in the vehicle group (21.9%). By visit 7, the incidence of angiographic CME had declined to between 4% and 8% and the incidence of clinical CME was less than 2% in all three groups. At visit 5, contrast sensitivity scores were significantly worse in vehicle-treated patients with angiographic CME than in those without CME, and Snellen visual acuity was one line worse in patients with CME. Flurbiprofen-treated patients achieved good Snellen visual acuity (better than 20/40) sooner than vehicle-treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1977

Serum concentrations of flurbiprofen in rheumatoid patients receiving flurbiprofen over long periods of time.

Serum concentrations of flurbiprofen were measured following single oral doses of 50 mg to 200 mg in patients who previously had received flurbiprofen over long periods of time. The apparent elimination half-lives in groups of patients who received different doses were not significantly different from each other nor from the value previously obtained in a group of healthy volunteers given a single oral dose of 50 mg. Areas under serum concentration versus time curves were linearly related to dose over the range of doses examined. The results indicate that the pharmacokinetics of flurbiprofen are not significantly dose-dependent over the range of doses studied and that administration of relatively high doses of flurbiprofen over long periods of time neither induces nor inhibits flurbiprofen metabolism.

Aged↗
PubMed1991

Effects of pure enantiomers of flurbiprofen in comparison to racemic flurbiprofen on eicosanoid release from various rat organs ex vivo.

The effects of oral treatment of rats with pure enantiomers of flurbiprofen in comparison to racemic flurbiprofen on ex vivo release of eicosanoids from gastric mucosa, jejunum, lung, brain and clotting whole blood were investigated. With the S(+) enantiomer and the racemate dose-dependent inhibition of release of cyclooxygenase products of arachidonate metabolism in all tissues tested was observed, while release of leukotriene (LT) C4 was inhibited in gastric mucosa, but not in jejunum and lung. On the other hand, the R(-) enantiomer inhibited cyclooxygenase in the various tissues less potently and to a variable degree with no significant effect in the jejunum. The R(-) enantiomer had no effect on LTC4 release from any of the tissues investigated. Furthermore, the effect of a high dose of 25 mg/kg of the S(+) enantiomer on release of cyclooxygenase products from the various tissues was much longer lasting than that of an identical dose of the R(-) enantiomer. Stereoselective pharmacokinetics of the flurbiprofen enantiomers and/or organ specific cyclooxygenase activities could underly these results. The more potent cyclooxygenase inhibition by the S(+) enantiomer correlates with its higher anti-inflammatory activity and gastrointestinal toxicity. On the other hand, both enantiomers have been shown previously to be almost equally effective analgesics. Inhibition of brain cyclooxygenase might contribute to this effect.

Animals↗
PubMed1993

Evaluation of flurbiprofen for prevention of reinfarction and reocclusion after successful thrombolysis or angioplasty in acute myocardial infarction. The Flurbiprofen French Trial.

Thirty-eight coronary care units (CCUs) in France participated in this double-blind, placebo-controlled, multicentre study to assess the efficacy of flurbiprofen, a non-steroidal anti-inflammatory agent (NSAID) with potent anti-platelet activity (PAA), in the prevention and recurrence of myocardial infarction (MI) and reocclusion of the infarct-related artery (IRA) in patients successfully treated for acute MI by thrombolysis and/or coronary angioplasty within 6 h of onset of symptoms. A coronary angiogram was performed within the first 24 h to confirm successful reperfusion. Two hundred and thirty-three patients (group 1) were randomly allocated to flurbiprofen 50 mg twice daily and 228 patients (group 2) to placebo. All patients complied with the entry criteria, and drug treatment was commenced within 48 h of MI. Patients were assessed at 3 weeks, 3 months and 6 months, data being recorded on major clinical events and survival status. Overall mortality was low (1.1%) and similar for both groups, confirming the benefit of early reperfusion therapy. The reinfarction rate documented during the 6-month follow-up was 3% (7/233) in group 1 and 10.5% (24/228) in group 2 (P < 0.001). The need for coronary angioplasty and/or coronary bypass graft was decreased by 51% (group 1: 39/233 = 17%; group 2: 75/228 = 33%) (P < 0.001). Coronary angiogram at 6 months showed a similar reocclusion rate between treatments. Flurbiprofen appears to be an effective drug for the prevention of reinfarction after coronary reperfusion and in reducing the need for secondary revascularization procedures. It may offer advantages over aspirin, but comparable efficacy remains to be established.

Adult↗
PubMed1996

Human plasma concentrations of R, S, and racemic flurbiprofen given as a toothpaste.

Flurbiprofen, an arylpropionic acid (APA) class nonsteroidal antiinflammatory drug (NSAID), is commercially available only as the racemic mixture, although its pharmacologic effect has been credited primarily to the S isomer. In humans, the bioavailability of racemic flurbiprofen absorbed from the oral cavity has been studied measuring the total concentration of S- and R-flurbiprofen, and the pharmacokinetics of S- and R-flurbiprofen have been studied after oral administration of racemic flurbiprofen. In this study, the plasma concentrations of S-flurbiprofen and to some extent R-flurbiprofen were studied after brushing with a toothpaste containing different mixtures of S- and R-flurbiprofen. The toothpaste formulations contained 1% racemic (50:50), eutectic (14:86), 1%, 0.5%, and 0.25% (5:95) R- to S-flurbiprofen. Both S- and R-flurbiprofen were rapidly absorbed, with a time to reach maximum concentration (tmax) of 1.2 to 1.4 hours. Based on the AUC, the amount of S-flurbiprofen absorbed increased proportionally when given as the 0.25% (5:95) preparation to the 0.5% (5:95) mixture but did not increase significantly above the 0.5% (5:95) mixture when given as 1% (5:95) R- to S-flurbiprofen. This suggests that dose-proportional absorption of S-flurbiprofen is not maintained at higher concentrations. The elimination of S-flurbiprofen appears to be variable and prolonged after this mode of administration, as observed from plasma concentrations. Further controlled and more prolonged studies of S- and R-flurbiprofen are needed to confirm these observations.

Adult↗
PubMed1988

Stereoselective pharmacokinetics of flurbiprofen in humans and rats.

Flurbiprofen, a 2-arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drug (NSAID), exists as racemate and is used as such. Although the activity of 2-APAs is due mainly to their S-enantiomers, information on the pharmacokinetics of flurbiprofen is usually based on the measurement of total concentrations of S- and R-flurbiprofen. In this work, the pharmacokinetics of flurbiprofen enantiomers following single doses were studied in humans and rats. Upon iv administration of 10 mg/kg of racemic flurbiprofen to male Sprague-Dawley rats, the plasma concentrations were consistently higher for S-flurbiprofen than for R-flurbiprofen (AUC = 134 +/- 39 versus 41 +/- 9 mg.L-1 h). In bile duct-cannulated rats, the biliary excretion contained only 3.6-5.2% of the dose as conjugated flurbiprofen (S:R = 1.2-2.1). After administration of R-flurbiprofen to the rat, both enantiomers were found in plasma [AUC(R):AUC(S) = 0.10-0.16], indicating a limited extent of enantiomeric bioinversion. This is consistent with the previously reported limited extent of flurbiprofen uptake into fat. In healthy volunteers also, significant stereoselectivity was observed in the plasma concentration of the drug after 100-mg oral racemic doses [AUC-(S):AUC(R) = 45.4 +/- 12.7:40.1 +/- 14.3 mg.L-1.h]. As compared with the R-enantiomer, S-flurbiprofen has a smaller volume of distribution (7.23 +/- 1.9 versus 8.41 +/- 3.0 L) and total clearance (1.23 +/- 0.34 versus 1.47 +/- 0.50 L/h), but an equal half-life (4.21 +/- 1.2 versus 4.18 +/- 1.3 h). In urine, on the other hand, the R-configuration was predominant, as greater amounts of the R-enantiomer were found both as conjugated flurbiprofen and as an unidentified metabolite. Negligible amounts of intact flurbiprofen enantiomers were detected in urine. The observed stereoselectivity in humans cannot be attributed to enantiomeric bioinversion, as S-flurbiprofen was not detected in plasma and urine after oral administration of R-flurbiprofen.

Administration, Oral↗
PubMed1997

Efficacy and tolerability of a topical NSAID patch (local action transcutaneous flurbiprofen) and oral diclofenac in the treatment of soft-tissue rheumatism.

The efficacy and safety of local action transcutaneous flurbiprofen 40 mg [flurbiprofen LAT] patches and diclofenac sodium tablets, 50 mg b.d., were compared in an open, multicentre, randomized, parallel-group study in patients with soft-tissue rheumatism. Patches were replaced at 12-hourly intervals. Clinical assessments were performed after 7 and 14 days of treatment. Fifty-six patients were treated with flurbiprofen LAT and 53 with diclofenac. Six withdrawals (three from each group) occurred during the treatment period. A statistically significant difference was observed in favour of flurbiprofen LAT for the principal measure, namely the investigator's opinion of overall change in clinical condition: 49/53 (92%) patients treated with flurbiprofen LAT had improved by day 14 compared with 36/49 (73%) patients receiving diclofenac sodium (p = 0.03; eligible dataset). There were also statistically significant differences in favour of flurbiprofen LAT for the investigator's assessments of the overall severity of the clinical condition (p = 0.03; eligible dataset), for the severity of pain at the region treated (p = 0.04; intent-to-treat), and for the severity of tenderness (p < 0.001; intent-to-treat). Supplementary analgesia (paracetamol) was required by two patients in the flurbiprofen LAT group and by eight diclofenac-treated patients. The difference in favour of flurbiprofen LAT in the average daily consumption of paracetamol was significant (p = 0.04). The patients' assessment of severity of pain on movement also favoured flurbiprofen LAT (p = 0.049; eligible dataset), but there were no statistically significant differences in day or night pain or quality of sleep. For the patients' opinion of treatment there was, however, a statistically significant difference in favour of flurbiprofen LAT (p = 0.02). Of the patients receiving flurbiprofen LAT, 94% regarded it as a convenient form of treatment. With respect to tolerability 8/56 (14%) patients applying flurbiprofen patches reported a total of nine adverse effects (AEs) (mainly local, mild skin irritations), vs 9/52 (17%) patients receiving diclofenac, who reported 12 AEs. Most AEs in the enteric-coated diclofenac group were of a gastrointestinal nature (one of which was severe). In terms of the proportion of patients reporting AEs related to the digestive system, there was a statistically significant difference in favour of flurbiprofen LAT (p = 0.011). In conclusion, local treatment of soft-tissue rheumatism with flurbiprofen LAT was demonstrably superior to benchmark oral therapy with diclofenac sodium over a 2-week period in terms of both efficacy and gastrointestinal tolerability. Flurbiprofen LAT provided both an effective and convenient form of topical SAID treatment.

Administration, Cutaneous↗
PubMed1996

New insights into the site and mode of antinociceptive action of flurbiprofen enantiomers.

The S-enantiomer of flurbiprofen has been shown to have both antiinflammatory and antinociceptive effects, whereas R-flurbiprofen is antinociceptive but not antiinflammatory. Importantly, only S-flurbiprofen inhibited prostaglandin biosynthesis in vitro at therapeutic concentrations. R-flurbiprofen did not undergo significant chiral inversion to S-flurbiprofen in rats and humans. A study was conducted to gain new insight into the possible sites and modes of action of flurbiprofen enantiomers. In a modified Randall Selitto assay, both enantiomers were antinociceptive in a dose-dependent manner after systemic administration. After local administration into the inflamed paw, only S-flurbiprofen produced significant dose-related antinociception. In a physiologic study, we recorded extracellularly from nociceptive spinal cord neurons that were rendered hyperexcitable. Intravenous administration of R- and S-flurbiprofen reduced responses of neurons to pressure applied to the inflamed knee and the noninflamed ankle and paw in a dose-dependent manner. When injected directly into the knee joint, only S-flurbiprofen but not R-flurbiprofen reduced responses to pressure. These results suggest a central site of antinociceptive action for R- and S-flurbiprofen and an additional peripheral site for S-flurbiprofen. The findings may be of clinical relevance, as it was demonstrated that both enantiomers also were antinociceptive in humans. Because R-flurbiprofen caused less toxicity in rats than the S-enantiomer or the racemic compound, a reduction in the quantitatively most important side effects in the gastrointestinal tract might be achieved with the use of R-flurbiprofen for pain therapy.

Analgesics↗
PubMed1984

Ocular and systemic bioavailability of ophthalmic flurbiprofen.

Flurbiprofen, a nonsteroidal antiinflammatory agent which is not ocularly metabolized, was employed as a probe compound to investigate the drug kinetic relationship between systemic and ocular humoral circulation. The ocular and systemic bioavailabilities of topically applied flurbiprofen were also quantitated. Anesthetized albino female rabbits received flurbiprofen doses intracamerally, topically, and intravenously at 2 to 4 week intervals. Aqueous humor and plasma were used as the sampling compartments. Plasma clearance values of flurbiprofen were 6.77 and 7.87 ml/min, after 6-mg and 208-micrograms intravenous doses, respectively. These values were not significantly different and indicated no dose-dependent disposition kinetics over a 30-fold dose range. Both ocular and systemic flurbiprofen dispositions followed a biexponential pattern with a rapid distribution phase. The systemic and ocular distribution half-lives of flurbiprofen were 12 min and 15 min, respectively. The plasma elimination half-life was 74 min and the aqueous humor elimination half-life was 93 min. The latter approximated the turnover rate of aqueous humor and suggested that aqueous humor drainage was the major process of flurbiprofen elimination from the globe. About 99% of flurbiprofen is bound to plasma protein. At distribution equilibrium, the plasma and aqueous humor concentrations of flurbiprofen differed by a hundredfold, suggesting that only free drug entered the aqueous humor after the administration of a systemic dose. In the ophthalmic studies, right eyes were instilled with 50 microliters of 0.3% flurbiprofen in saline (dose = 150 micrograms), and left eyes were instilled with 50 microliters of 0.15% flurbiprofen in saline (dose = 75 micrograms). When the area of the aqueous humor concentration-versus-time curve values was normalized by the administration dose, the 75-micrograms dose was 30% more available to ocular tissues than was the 150-micrograms dose. This demonstrated a disproportionate relationship between the administered dose and the fraction absorbed. The intracameral dose was considered to be completely bioavailable for intraocular effects. The ocular bioavailability of the ophthalmic dose was defined by using intracameral administration as a standard measurement. The ocular bioavailabilities of the 75-micrograms and 150-micrograms topical flurbiprofen doses were 10% and 7%, respectively. Systemic bioavailability after topical administration of 225 micrograms of flurbiprofen was 74%.

Administration, Topical↗
PubMed1990

Influence of H2 receptor antagonists on the disposition of flurbiprofen enantiomers.

The effect of oral cimetidine or ranitidine on the pharmacokinetics of the R and S enantiomers of the nonsteroidal anti-inflammatory drug flurbiprofen and its major metabolite, 4'-hydroxyflurbiprofen, was evaluated. Nine healthy volunteers participated in a randomized crossover design study with the following treatments: (A) flurbiprofen 200 mg; (B) flurbiprofen 200 mg plus ranitidine 150 mg bid for 7 days before and for 2 days after receiving flurbiprofen and (C) flurbiprofen 200 mg plus cimetidine 300 mg qid for 7 days before and for 2 days after receiving flurbiprofen. Blood and urine samples were collected at various intervals during a 48-hour period. These samples were assayed stereospecifically for flurbiprofen and its metabolite. Small but statistically significant differences in the terminal elimination rate constant (K), maximum peak serum drug concentration (Cmax), time to reach peak concentration (tmax), oral clearance (Cl/F) and area under the curve (AUC) were noted for flurbiprofen enantiomers. No significant treatment*isomer interactions were observed, indicating that neither cimetidine nor ranitidine interacted stereospecifically with flurbiprofen. Cimetidine, but not ranitidine, resulted in small (less than or equal to 15%) but statistically significant changes in flurbiprofen pharmacokinetic parameters. The interaction between H2-antagonists and flurbiprofen is unlikely to be clinically important.

Adult↗
PubMed1995

Role of cytochrome P450 2C9 and an allelic variant in the 4'-hydroxylation of (R)- and (S)-flurbiprofen.

Flurbiprofen is a chiral non-steroidal anti-inflammatory drug used in the treatment of pain or inflammation. The primary routes of biotransformation for (R)- and (S)-flurbiprofen are oxidation (presumably cytochrome P450) and conjugation. To date, the specific cytochrome P450 (P450) involved in the oxidative metabolism of this compound (specifically 4'-hydroxylation) has not been elucidated. Experiments were conducted to characterize the kinetic parameters (Km and Vmax) for the 4'-hydroxylation of (R)- and (S)-flurbiprofen in human liver microsomes, to determine if enantiomeric interactions occur when both enantiomers are present, and to identify the specific P450 form(s) involved in this reaction. In human liver microsomes, the Km and Vmax (mean +/- SD) for (R)-4'-hydroxy-flurbiprofen formation were 3.1 +/- 0.8 microM and 305 +/- 168 pmol.min-1.mg protein)-1, respectively. In comparison, the Km and Vmax (mean +/- SD) for (S)-4'-hydroxy-flurbiprofen formation were 1.9 +/- 0.4 microM and 343 +/- 196 pmol.min-1.mg protein-1, respectively. Enantiomeric interaction studies revealed a decrease in Km and Vmax for both enantiomers and an apparent loss of stereoselectivity. Racemic-warfarin, tolbutamide, alpha-naphthoflavone and erythromycin were studied as potential inhibitors of this process. The estimated Ki values for the inhibition of (R)- and (S)-4'-hydroxy-flurbiprofen formation by racemic-warfarin were 2.2 and 4.7 microM. This reaction was also inhibited by tolbutamide. In contrast, erythromycin and alpha-naphthoflavone had no appreciable effect on 4'-hydroxy-flurbiprofen formation. cDNA-expression of individual forms was used to determine which P450 was involved in 4'-hydroxy-flurbiprofen formation. P450 2C9 and an allelic variant (R144C) readily catalyzed the formation of 4'-hydroxy-flurbiprofen. P450 1A2 was also active albeit with a turnover rate 1/140th that of P450 2C9R144C (P450s 2C8, 2E1 and 3A4 were not active toward either enantiomer). The results of these studies indicate that the enantiomers of flurbiprofen may exhibit stereoselectivity with respect to enzyme affinity but have roughly equal maximum formation velocities. Additionally, these two enantiomers may compete for the enzyme resulting in lower maximum velocities for both enantiomers. Finally, of those P450 forms examined, only P450 2C9 and an allelic variant catalyzed the 4'-hydroxylation of both (R)- and (S)-flurbiprofen.

Aryl Hydrocarbon Hydroxylases↗
PubMed1997

Disposition and effects of flurbiprofen enantiomers in human serum and blister fluid.

AIMS: To investigate the pharmacokinetics of the enantiomers of flurbiprofen and inhibition of prostanoid production in blister fluid and serum. METHODS: Eleven healthy volunteers received 75 mg R-, 75 mg S-flurbiprofen or no medication in a randomized 3-way cross-over study. Flurbiprofen concentrations were determined by h.p.l.c. TXB2 and PGE2 were determined by enzyme immunoassay and chemiluminescence immunoassay respectively. RESULTS: S-flurbiprofen produced almost complete (> 99% vs baseline) inhibition of thromboxane B2 (TXB2) in serum in all volunteers and significant inhibition of prostaglandin E2 (PGE2) generation in blister fluid, but there was a considerable inter-individual variation in the response ranging from -78 to +190% change from control PGE2 AUC. After administration of R-flurbiprofen, there was a mean maximum TXB2 inhibition of 65.2 +/- 15.0% in serum but no significant changes of PGE2 levels in blister fluid were observed. The pharmacokinetic parameters in serum and blister fluid were not significantly different between enantiomers. R- to S-inversion did not occur to a clinically relevant extent. For R-flurbiprofen, the complex rate constant of transfer into blister fluid was greater at the u.v.-exposed site (0.110 +/- 0.050) than at the control site (0.079 +/- 0.026, P < 0.05) which corresponded to a higher AUC and Cmax of R-flurbiprofen in u.v.-exposed blister as compared with control. For inhibition of TXB2 generation after administration of S-flurbiprofen, a sigmoidal log-linear concentration-response relationship was established in all subjects (EC50: 0.123 +/- 0.092 microgram ml-1). In contrast, inhibition of PGE2 production in blister showed no clear concentration-response relationship when correlated with concentrations of S-flurbiprofen in either serum or blister fluid. After administration of R-flurbiprofen, no concentration-effect relationship could be established. CONCLUSIONS: It is concluded that the blister model may have value for studying the pharmacokinetics and pharmacodynamics of antiinflammatory drugs in humans. Interestingly, inter-individual variation in the pharmacokinetics of flurbiprofen enantiomers could not account for the variability in response observed in the blister model.

Adult↗
PubMed1997

Intestinal tolerability of nitroxybutyl-flurbiprofen in rats.

BACKGROUND: Nitric oxide derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) are thought to be much less ulcerogenic than their parent compounds. AIM: To compare the effect and potency of flurbiprofen and nitroxybutyl-flurbiprofen to uncouple mitochondrial oxidative phosphorylation (an early pathogenic event in NSAID enteropathy), increase intestinal permeability (transitional stage), and cause macroscopic small intestinal damage. METHODS: In vitro uncoupling potency was assessed using isolated coupled rat liver mitochondria and in vivo by electron microscopy of rat small intestinal mucosa (two hours after the drugs). A dose-response study with flurbiprofen (single doses of 5, 10, 20, and 40 mg/kg) and equimolar doses of nitroxybutyl-flurbiprofen was performed; assessing their effect on intestinal permeability (at 18-20 hours), with 51Cr EDTA, and the number of pointed (< 5 mm) and longitudinal (> 5 mm) small intestinal ulcers at 24 hours. RESULTS: Flurbiprofen, but not nitroxybutyl-flurbiprofen, stimulated coupled respiration in vitro. Both drugs, however, uncoupled in vivo; in the case of nitroxybutyl-flurbiprofen possibly because hydrolysis of its ester bond released free flurbiprofen. Intestinal permeability was uniformly and equally increased with both drugs compared with controls. The number of small intestinal ulcers, pointed and longitudinal, was significantly reduced with nitroxybutyl-flurbiprofen apart from the number of longitudinal ulcers with the highest dose. CONCLUSIONS: These studies show that nitroxybutyl-flurbiprofen is associated with significantly less macroscopic damage in the small intestine than flurbiprofen but was associated with mitochondrial damage in vivo and caused similar increases in permeability of the small intestine, suggesting that its beneficial effect is on the later pathogenic stages of the damage.

Animals↗
PubMed1986

Effects of cimetidine or ranitidine on the pharmacokinetics of flurbiprofen.

The effect of oral cimetidine or ranitidine on the pharmacokinetics of the nonsteroidal anti-inflammatory agent flurbiprofen was studied. Nine healthy volunteers participated in the study. The subjects were divided into three groups, and each group alternated therapy with each of the following treatments: flurbiprofen 200 mg (two 100-mg tablets), flurbiprofen 200 mg plus ranitidine 150 mg two times daily for seven days before and for two days after receiving flurbiprofen, and flurbiprofen 200 mg plus cimetidine 300 mg four times a day for seven days before and for two days after receiving flurbiprofen. Blood samples were collected at time zero and at various intervals during a 48-hour period. Serum flurbiprofen concentrations were determined by high-performance liquid chromatography. No significant differences in elimination rate constant, peak concentration, time to peak concentration, volume of distribution, or elimination half-life were noted among treatments. The difference in area under the curve (AUC) in subjects treated with flurbiprofen alone and in those treated with flurbiprofen plus cimetidine was significant. Two subjects experienced gastric upset; one case was apparently caused by cimetidine, and the other was likely caused by flurbiprofen. Although a significant increase in AUC was observed in subjects receiving flurbiprofen plus cimetidine, the interaction is probably not clinically important.

Adult↗
PubMedDate not supplied

Pharmacokinetic interaction between flurbiprofen and antacids in healthy volunteers.

Gastrointestinal distress resulting from drug intake is often remedied by administering the drug with antacids. However, antacids have been shown to modify the absorption and excretion of many drugs. This study was designed to delineate the effects of aluminium and magnesium hydroxide antacid suspension (Maalox) on the pharmacokinetics of flurbiprofen. Since this drug is often used in the elderly, not only young healthy but also geriatric healthy male volunteers participated in the study. A group of twelve young and a group of seven geriatric volunteers received, in a crossover design, a single oral dose of 100 mg of flurbiprofen with and without Maalox. A non-stereospecific assay was used to determine the total (R + S enantiomers) of flurbiprofen in plasma. The relative pharmacokinetic parameters of total flurbiprofen determined from plasma samples were Cmax, tmax, Kel, t1/2, and AUC infinity. The results indicate that the co-administration of Maalox with flurbiprofen had no effect on the rate and extent of total flurbiprofen absorption in young volunteers. In geriatric volunteers, the results indicate no effect of the antacid on the extent of drug absorption. There was a trend for lower plasma concentrations of total flurbiprofen with antacid in the geriatric group and hence a reduction in rate of flurbiprofen absorption although differences were not significant. The study also included a steady state determination of the influence of antacid administration on flurbiprofen pharmacokinetics. The group of young volunteers received, from Day 3 to Day 8, 100 mg of flurbiprofen every 12 h with and without Maalox.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Clinical pharmacokinetics of flurbiprofen and its enantiomers.

Flurbiprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class. Although it possesses a chiral centre, with the S-(+)-enantiomer possessing most of the beneficial anti-inflammatory activity, both enantiomers may possess analgesic activity and all flurbiprofen preparations to date are marketed as the racemate. Flurbiprofen exhibits stereoselectivity in its pharmacokinetics. Stereoselectivity is exhibited at the level of protein binding and metabolite formation. Hence, the data generated using nonstereoselective assays may not be used to explain the pharmacokinetics of individual enantiomers. The absorption of flurbiprofen is rapid and almost complete when given orally. The area under the plasma concentration-time curve of flurbiprofen is proportional to the dose administered to patients. Sustained release dosage forms are available, which may be beneficial due to the short terminal phase elimination half-life of conventional immediate release flurbiprofen (3 to 6 hours). They may also decrease local gastrointestinal adverse effects. Although with these preparations the peak plasma drug concentration is reduced and time taken to achieve peak concentrations is prolonged, the bioavailability is the same as that with regular release counterparts. Flurbiprofen binds extensively to plasma albumin, apparently in a stereoselective manner. Substantial concentrations of the drug are attained in synovial fluid, which is the proposed site of action of NSAIDs. There is negligible R to S inversion after oral administration. Flurbiprofen is eliminated following extensive biotransformation to glucuro-conjugated metabolites. Conjugates are excreted in urine, and approximately 20% of flurbiprofen is eliminated unchanged. The excretion of conjugates may be tied to renal function as accumulation of conjugates occurs in end-stage renal disease, but not in young individuals or elderly patients. Although flurbiprofen is excreted into breast milk, the amount of drug transferred comprises only a small fraction of the maternal exposure. Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), coumarins and propranolol. The relationship between concentration and anti-inflammatory and analgesic effect has yet to be elucidated for this drug.

Absorption↗
PubMed1995

Antinociceptive effects of R(-)- and S(+)-flurbiprofen on rat spinal dorsal horn neurons rendered hyperexcitable by an acute knee joint inflammation.

The antinociceptive effects of the S(+)-enantiomer of flurbiprofen (potent inhibitor of cyclooxygenase) and the R(-)-enantiomer (500 times less potent) were investigated in the spinal cord of 20 anesthetized rats. In lumbar segments, 20 wide-dynamic-range dorsal horn neurons with knee joint input were recorded extracellularly. After induction of an acute inflammation in the knee joint by kaolin and carrageenan, the neurons developed hyperexcitability consisting of enhanced responses to stimuli applied to the inflamed knee and the noninflamed ankle and an expansion of receptive fields. Intravenous administration of R(-)-flurbiprofen (1-9 mg/kg) and S(+)-flurbiprofen (0.3-9 mg/kg) at 5.5 to 8.5 h after kaolin, dose dependently reduced the neurons' responses to pressure applied to the inflamed knee (18 of 18 neurons) and the noninflamed ankle (17 of 17 neurons) and paw (8 of 8 neurons). R(-)-flurbiprofen decreased the receptive field size in 8 of 16 neurons, S(+)-flurbiprofen in 10 of 16 neurons. The suppressive effects started 3 to 6 min and reached a maximum 9 to 15 min after i.v. administration. S(+)-flurbiprofen was more potent than the R(-)-enantiomer. When injected directly into the knee joint, S(+)-flurbiprofen (50 and 80 micrograms), but not the R(-)-enantiomer (100 and 180 micrograms) reduced the hyperexcitability in 12 of 12 neurons. These results suggest a central site of antinociceptive action for R(-)-flurbiprofen and S(+)-flurbiprofen and an additional peripheral site for S(+)-flurbiprofen. The doses used in these experiments did not produce any sedative effects in rats subjected to behavioral testing.

Analgesics↗