Absorption Of Ketoprofen Research Articles

Bioavailability of S(+)-Ketoprofen After Oral Administration of Different Mixtures of Ketoprofen Enantiomers to Dogs.

Recent reports have disagreed on whether the bioavailability of S(+)-ketoprofen is affected by the presence of R(-)-ketoprofen. To examine this directly, we designed a randomized crossover study in beagle dogs. [14 C]- S(+)-ketoprofen trometamol and R(-)-ketoprofen trometamol were administered in the following percentage ratios: A, 99:1; B, 95:5; C, 90:10; D, 70:30; E, 50:50. Treatments were administered as a single oral dose of 1 mg/kg trometamol salt. Each of eight dogs received all five combinations in random order with a 1-week washout period between doses. Blood samples were taken before drug administration and at regular intervals for 240 min after dosing. A progressive increase in the plasma concentration of [14 C]-S(+)-ketoprofen was observed on going from treatment E (lowest dose of S-enantiomer) to treatments containing the highest doses of (14 C]-S(+)-ketoprofen. When the pharmacokinetic calculations were normalized to the dose of (14 C]-S(+)-ketoprofen, we found no statistically significant differences among the normalized AUC and Cmax values of the five treatments. Therefore, S(+)-ketoprofen absorption was linear and was not influenced by the presence of R(-)-ketoprofen. Furthermore, there were no significant differences in tmax values among treatments, indicating that the rate of S(+)-ketoprofen absorption was also unaffected by the presence of R(-)-ketoprofen.

Enhancement of percutaneous absorption of ketoprofen: effect of vehicles and adhesive matrix

The effects of various vehicles on percutaneous absorption of ketoprofen in a solution formulation and in a pressure-sensitive adhesive (PSA) matrix were evaluated. The permeation rate of ketoprofen across hairless mouse skin was evaluated using a flow-through diffusion cell system at 37°C. The solubility of ketoprofen was determined using the equilibrium solubility method. Among tested vehicles, octanol, ethanol, and propylene glycol (PG)/oleyl alcohol (OA) mixture showed the highest flux of 30 μg/cm 2 per h from 5 mg/ml solution. However, it was not possible to demonstrate any correlation between the solubility of ketoprofen and its permeation rate, indicating change in the barrier property of the skin and/or carrier mechanism by vehicles used. When the effects of various vehicles on the percutaneous absorption of ketoprofen from acrylic PSA matrix were evaluated, oleic acid showed a slightly higher flux of 2 μg/cm 2 per h than all other solvents tested. As the concentration of ketoprofen in acrylic PSA matrix increased from 6.3 to 16.7%, the permeation rate also increased almost linearly. The permeation rate of ketoprofen from polyisobutylene (PIB)-type PSA matrix was more than three times higher than that from acrylic PSA matrix.

EFFICACY OF A NEW TOPICAL GEL-SPRAY FORMULATION OF KETOPROFEN LYSINE SALT IN THE RAT: PERCUTANEOUS PERMEATIONIN VITROANDIN VIVOAND PHARMACOLOGICAL ACTIVITY

The aim of this study was to evaluate the percutaneous permeation of a new topical Gel-Spray formulation, containing 15% of ketoprofen lysine salt (KLS), bothin vitro, using the Franz-type diffusion cells andin vivo, by evaluating urinary recovery after topical administration and to correlate the absorption data with KLS pharmacological activity in the rat. Concentrations of ketoprofen free acid (KFA) were determined by HPLC in the receptor compartment (in vitro), or in urine (in vivo). The permeation of ketoprofen evaluatedin vitroafter the application of KLS Gel-Spray was higher than that observed with the marketed formulation Profénid gel (containing KFA at 2.5%). The same evidence was foundin vivo, except when the ratio between the administered dose and the area treated was higher than 1 mg cm−2. Thus, the difference between the two formulations seems to be the resultant of two opposing components: a positive gradient of concentration that favours the absorption of ketoprofen from KLS Gel-Spray and the presence of the enhancer ethanol that could favour the efficacy of Profénid gel. Under our conditions the former prevailed. As for the efficacy, evaluated in the carrageenan-induced oedema and hyperalgesia model, KLS Gel-Spray confirmed the data obtained forin vivoabsorption, being more efficient than the reference standard Profénid gel. The observed inhibitory effects were due only to dermal absorption, oral absorption was excluded by an Elizabethan collar applied around the neck of the rat. In these experimental conditions, no significant damage of the rat stomach mucosa was observed. These results indicate that KLS Gel-Spray, due to its high KLS concentration, allows a very high efficiency in delivering ketoprofen to the inflamed area using a minimal amount of formulation, even in the absence of permeation enhancers.

Effects of Cyclodextrin Derivatives on Bioavailability of Ketoprofen

In order to develop a new oral dosage form of ketoprofen with enhanced dissolution rate and bioavailability, inclusion complexes of ketoprofen with cyclodextrin derivatives such as α-cyclodextrin, β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and dimethyl-β-cyclodextrin were prepared using a spray dryer, and comparative studies on the in vitro dissolution and in vivo absorption of ketoprofen were carried out. Ketoprofen in the inclusion complexes was completely dissolved within 5 min. On the other hand, only about 50.1% of ketoprofen powder alone dissolved in 60 min. The initial dissolution rates of ketoprofen in the inclusion complexes markedly increased in distilled water at 37°C, which were over 5-fold higher than that of powder alone. The maximal plasma concentration of ketoprofen (Cmax) and area under concentration-time curve (AUC0→8h) after the oral administration of inclusion complexes increased about 6-fold (46.69 or 45.36 vs. 7.55 μ/ml) and 3-fold (44.41 or 50.14 vs. 17.33 μ hr/ml) compared to those of powder alone. It was obvious that ketoprofen inclusion complex might be a useful solid dosage form in improving the dissolution rate and bioavailability of poorly water-soluble ketoprofen.

Promoting effect of O-ethylmenthol on the percutaneous absorption of ketoprofen

The promoting effect of O-ethylmenthol (MET) on the percutaneous absorption of ketoprofen from alcoholic hydrogels was evaluated in rats in vitro and in vivo. Further, the anti-inflammatory action of ketoprofen hydrogels was evaluated with a rat paw edema test. The time course of the cumulative amounts of drug permeated through the rat skin in vitro exhibited a linear relation after an initial time lag. This was analyzed in a membrane diffusion model and the diffusion and partition parameters of ketoprofen were estimated. Both parameters were remarkably enhanced when a hydrogel containing a small quantity of MET (0.5%) was applied. However, at least 2% menthol was required to obtain the same activity as 0.25% MET. A pharmacokinetic model, which was derived on the assumption of a constant penetration rate ( R p) after a lag time, was employed to evaluate in vivo percutaneous absorption of ketoprofen from hydrogels containing MET. Further, the area under the plasma concentration-time curve (AUC 0–8 h) was estimated. Similarly to the results observed in vitro, R p and AUC 0–8 h values were increased significantly by the administration of hydrogels containing a small amount of MET (0.25–0.5%). In order to obtain the significant inhibitory action of ketoprofen on the rat paw edema induced by carrageenan, at least 1% menthol was required in the hydrogel formulation. On the other hand, a small amount of MET (0.25–0.5%) was enough to bring about significant inhibitory action of ketoprofen. Distinguishable changes of the skin surface were microscopically observed with 0.5–2% MET, i.e. the spaces between the stratum corneum cells became extended and the shape of each cell became clear, whereas the morphological changes caused by menthol were relatively weak. Both MET and menthol may change the dense barrier structure of the stratum corneum of skin; however, the efficiency of MET is significantly greater than that of menthol.

Percutaneous absorption of ketoprofen. I. In vitro release and percutaneous absorption of ketoprofen from different ointment bases

Ketoprofen (KP) is a potent non-steroidal anti-inflammatory drug which is used for the treatment of rheumatoid arthritis. The oral administration of KP can cause gastric irritation and renal adverse effects. Topical application of the drug can bypass gastrointestinal disturbances and provide relatively consistent drug levels at the site of action. Since the efficacy of an ointment depends on the type of ointment base and the concentration of the drug, four different bases (white petrolatum, cold cream, hydrophilic ointment and Carbopol 940 gel) were used at 1, 3, 5, 7 and 10% concentrations of KP to evaluate the effect of ointment base and concentration. The general rank order of the drug release was found to be: Carbopol gel > hydrophilic ointment > cold cream > white petrolatum. There was a positive correlation between the concentration of KP and release rate for all bases except Carbopol gel. The in vivo percutaneous absorption of KP from different ointment bases at 3% concentration was studied by carrageenan-induced paw edema in mice. The rank order of the percent edema inhibition was as follows: Carbopol gel ≥ hydrophilic ointment > cold cream > white petrolatum. There was a good correlation between the in vitro and in vivo results.

ケトプロフェンの経皮吸収に及ぼす入浴および貼付タイミングの影響

ケトプロフェンの経皮吸収に及ぼす入浴および貼付タイミングの影響

Combined effect of d-limonene and temperature on the skin permeation of ketoprofen

The effect of temperature on the enhancement action of d-limonene on percutaneous absorption of ketoprofen (KPF) was investigated in rats in vivo and in vitro. The apparent penetration rate ( R p ) of KPF absorbed from alcoholic hydrogels in rats was estimated based on a pharmacokinetic model, which was derived on the assumption of a constant penetration rate through the skin. The R p value increased sigmoidally with increase in the temperature applied, i.e., the R p value was almost constant at the lower temperatures, however, it increased abruptly at the critical temperature ( T c ) of applied heat. The T c value was significantly lowered by increasing the content of d-limonene in the hydrogel. The steady-state permeability coefficients ( P) of KPF through the skin was determined by employing two-chamber diffusion cells in which the excised rat abdominal skin was mounted. The combined effect of d-limonene and temperature on the P value was also clarified. The Arrhenius plots of P values showed a linear relationship when the skin was pretreated with 30% ethanol without d-limonene. The activation energy of permeation of KPF through the skin was estimated to be 6.49 kJ/mol. When the skin was pretreated with 1.5% d-limonene in 30% ethanol, the Arrhenius plots of P exhibited a convex curvature. Morphological changes of the skin surface were also observed microscopically. The application of heat, along with the synergistic effect of d-limonene, may effectively change the dense barrier structure of the stratum corneum.

Effects of the Administration of Ketoprofen gel on the Percutaneous Absorption of Ketoprofen in Rabbits

AbstractThe effects of the administration for a commercial keto-profen gel on the percutaneous absorption of ketoprofen (through rabbit abdominal skin) were investigated. The AUC (area under the curve) value of absorbed ketoprofen for single topical administration of 6 g of ketoprofen gel applied with ODT (occlusive dressing technique) was found to be about 6 -fold greater than that of repeated administration of 1.5 g of ketoprofen gel applied with ODT at 6 h interval in a day. It was about 14-fold greater than that of repeated administration of 1.5 g of ketoprofen gel applied without ODT at 6 h interval in a day. The experiment of volatilation of ketoprofen gels and the in vitro release test of ketoprofen gel applied with ODT and without ODT had been, in addition, respectively approached. The volatilation of solvent in the gel, as a result of this, may clearly be the primary factor for inducing a sharp descending of the plasma ketoprofen level following the Cmax (maximun concentration) in the in vivo per...

Effect of metoclopramide on ketoprofen pharmacokinetics in man

The effect of oral administration of metoclopramide (10 mg) on the absorption of ketoprofen from a capsule dosage form (50 mg) was studied in four healthy subjects in a cross-over design. The plasma concentrations of ketoprofen were determined by a HPLC technique. The results demonstrated a marked decrease in drug levels during coadministration with metoclopramide in the first 2 h post-dose. Metoclopramide resulted in markedly lower AUC and C max values with a longer T max of ketoprofen in comparison with the corresponding values for the drug alone. The results suggest that the gastric phase of ketoprofen absorption is the determinant step of the process. Rapid transit of the capsule, due to metoclopramide, reduces the time required for adequate dissolution and absorption.

Percutaneous absorption of ketoprofen from acrylic gel patches containing d-limonene and ethanol as absorption enhancers.

The percutaneous absorption of ketoprofen (KPF) from gel patches containing d-limonene and ethanol was investigated in rats. Plasma levels of KPF varied with the kind of polymers which constitute the gel patch, and the highest level was observed when the copolymer of ethylacrylate (EA) and diethyleneglycolmethacrylate (DEGMA) was used as a vehicle. The amount of KPF permeating through the rat skin from the gel patch was well correlated with that of ethanol. Permeations were enhanced with increase in the amount of d-limonene distributed from the vehicle to the skin tissue. The amount of d-limonene accumulated in the skin varied greatly with the kind of polymers; the highest accumulation was observed with the EA-DEGMA copolymer, and decreased with increasing affinity of d-limonene to the polymers. The reason EA-DEGMA copolymer showed the highest percutaneous absorption of KPF from gel patches containing d-limonene may be the hydrophilic nature of this polymer which showed the lowest affinity to d-limonene.

The effect of magnesium hydroxide on the oral absorption of ibuprofen, ketoprofen and diclofenac.

1. The effect of magnesium hydroxide on the oral absorption of ibuprofen, ketoprofen and diclofenac was investigated in two randomized cross-over studies, both consisting of two phases. 2. Single doses of magnesium hydroxide (850 mg) or of water (150 ml) only were given to six healthy volunteers immediately after the ingestion of ibuprofen (400 mg, Study 1), ketoprofen (50 mg, Study 2) or diclofenac (50 mg, Study 2). Plasma drug concentrations were measured up to 24 h. 3. Magnesium hydroxide increased the area under the plasma ibuprofen concentration-time curve between 0 and 1 h by 65% (P less than 0.05) and the peak concentration of ibuprofen in plasma by 31% (P less than 0.01). The time to peak was shortened by about 0.5 h. The extent of bioavailability of ibuprofen was not increased by magnesium hydroxide. 4. Neither the rate nor the extent of absorption of ketoprofen or diclofenac was changed significantly by magnesium hydroxide. 5. When rapid onset of the analgesic effect of ibuprofen is required, concomitant ingestion of an antacid, which contains magnesium hydroxide without aluminium, is recommended.

Clinical Pharmacokinetics of Ketoprofen and Its Enantiomers

Ketoprofen, a potent nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class, has been used clinically for over 15 years in Europe, and has recently been introduced in the United States. Although it possesses a chiral centre, with only the S-enantiomer possessing beneficial pharmacological activity, all ketoprofen preparations to date are marketed as the racemate. Ketoprofen exhibits little stereoselectivity in its pharmacokinetics. The enantiomers have similar plasma time-courses and do not seem to interact with one another. Hence, the data generated using nonstereospecific assays may be used to explain the pharmacokinetics of individual enantiomers. The absorption of ketoprofen is rapid and almost complete when given orally. Sustained release dosage forms are available, which may be beneficial due to the short terminal phase half-life of ketoprofen (1 to 3h). They may also decrease local gastrointestinal side effects. Although with these preparations the peak plasma drug concentration is reduced and time to peak is prolonged, the bioavailability is the same as that with regular release counterparts. Ketoprofen binds extensively to plasma albumin, apparently in a stereoselective manner. Substantial concentrations of the drug are attained in synovial fluid, the proposed site of action of NSAIDs. It is eliminated following extensive biotransformation to inactive glucuroconjugated metabolite. There is about 10% R to S inversion upon oral administration. Conjugates are excreted in urine, and virtually no drug is eliminated unchanged. The excretion of conjugates is closely tied to renal function; accumulation of conjugates occurs in the elderly, but not in young subjects or patients. Significant drug interactions have been demonstrated for probenecid, aspirin and methotrexate. There appears to be circadian variation, particularly in the absorption of ketoprofen. The relationship between concentration and anti-inflammatory effect has yet to be elucidated for this drug.

Biopharmaceutical evaluation of ketoprofen following intravenous, oral, and rectal administration in dogs

The influence of the hydrophilicity of three suppository bases on the rectal absorption of ketoprofen was studied. Absorption characteristics of ketoprofen were compared after intravenous, oral, and rectal administrations of 100 mg of drug given in a crossover design to five dogs. Rectal formulations included an aqueous solution and three suppository formulations. After oral dosing, ketoprofen was rapidly absorbed (time of maximum concentration, tmax: 0.83 ± 0.61 h), and a comparison with the intravenous solution indicated a complete bioavailability of 0.90 ± 0.10. After rectal administration, the rate of absorption, as evaluated with tmax and mean absorption time, was always slower than after oral dosing. A high variability was observed in the plasma concentrations obtained with suppository formulations; bioavailability values were ~20% lower than those from the oral solutions. No statistical difference in bioavailability and peak concentrations between the three suppository formulations was observed. Time of peak concentrations, mean absorption times, and fractions of the dose absorbed 6 h post administration did not show a difference in rate of ketoprofen absorption from the three suppository formulations. This study did not reveal a relationship between rate and extent of ketoprofen rectal absorption and the hydrophilicity of the suppository bases tested.

Effects of food and sucralfate on the pharmacokinetics of naproxen and ketoprofen in humans

Compliance to nonsteroidal anti-inflammatory drug therapy can be compromised by gastrointestinal side effects. To overcome this problem, food, antacid, or sucralfate are often co-administered with nonsteroidal anti-inflammatory drugs. Three studies were conducted on three groups of 12 volunteers in order to determine the influence of food or sucralfate on the pharmacokinetics of naproxen and ketoprofen. In a crossover experimental design, the first group received a single dose (50 mg) of ketoprofen with and without sucralfate (2 g). The second group received single (100 mg) and multiple (100 mg twice daily for 5 days) doses of enteric-coated ketoprofen with and without food. The third group received single (500 mg) and multiple (500 mg twice daily) doses of naproxen with and without sucralfate. Multiple blood samples were drawn and analyzed by high-pressure liquid chromatography. Short- and long-term pharmacokinetic parameters were determined. Results in group 1 showed that neither ketoprofen bioavailability nor maximal plasma concentration and time to reach maximal concentration were affected by the administration of sucralfate. However, in group 2 absorption of ketoprofen was markedly affected by food. In the presence of food, maximal plasma concentration decreased from 10.7 to 6.3 μg/ml after single-dose administration and 12.1 to 8.0 μg/ml after multiple-dose administration. The time to reach maximal plasma concentration was also modified by food, increasing from 2.8 to 7.1 hours after single-dose and 2.8 to 7.6 hours after multiple-dose administration. Food caused a significant decrease in the bioavailability of ketoprofen (over 40 percent) following both single-dose (23.8 versus 13.1 μg · hour/ml) and multiple-dose (29.3 versus 16.8 μg · hour/ml) administration. Results obtained in group 3 showed that sucralfate reduced the absorption rate constant of naproxen, from 1.7 to 1.2 hours −1 and from 1.5 to 0.7 hour −1 following single- and multiple-dose administration, respectively. However, bioavailability of naproxen was not affected by sucralfate administration. Overall, these studies have shown that sucralfate does not alter the pharmacokinetics of naproxen and ketoprofen; the amount of drug absorbed remains constant. However, plasma concentrations of ketoprofen after single- and multiple-dose administration were greatly affected by food, with a decrease of greater than 40 percent in bioavailability.

Inter-subject variation in oral absorption of ketoprofen from controlled-release granules in rabbits

Three kinds of controlled-release granules of ketoprofen were prepared. The release rate of granules A was controlled by ethylcellulose (EC) and was increased with increasing the pH value in the medium. The release rates of granules B and granules C were controlled by EC, hydroxypropyl methylcellulose (HPMC) and Eudragit E100. Granules B released the drug rapidly at pH 5 and 6 in the medium, while the release from granules C was less influenced by the pH value in the medium than those from granules A and granules B. We used gastric-acidity-controlled rabbits to evaluate the variation in the absorption after oral administration of these granules. Plasma levels after administration of 3 kinds of controlled-release granules to the non-treatment group were prolonged compared with those of the commercial capsule. There were no statistically significant differences in AUC 0–24 h between each granular formulation and the commercial capsule. There were statistically significant differences in C max or T max between the high and the low gastric acidity groups after administration of granules A or granules B, while there were no statistically significant differences in C max, T max and AUC 0–24h between high and low gastric acidity groups after administration of granules C. It was indicated that pH-independent controlled-release granular formulation would be one of the useful dosage forms which could potentially reduce the inter-subject variations in absorption.

Effect of milk and food on the bioavailability of ketoprofen in man

The influence of milk and of a standard breakfast on ketoprofen bioavailability from commercial capsules was studied in 4 healthy volunteers. The drug was administered as a single oral dose of 50 mg. Evaluation of the absorption rate was done by means of urinary excretion measurements. Eight urine samples were collected over a 24-h period following ketoprofen administration and the drug urine concentrations were determined by HPLC. The data were statistically analyzed by the t-test for paired observations. Milk significantly reduced the extent of ketoprofen absorption, while both the rate and extent of absorption were significantly reduced by food.

The effect of food on the systemic availability of ketoprofen.

We have studied the pharmacokinetics of ketoprofen, a non-steroidal anti-inflammatory drug, in 12 patients after a single 100 mg oral dose both in fasting conditions and with a meal. Food significantly affected the peak plasma concentration of ketoprofen and decreased its absorption rate. However, the extent of absorption of ketoprofen, as reflected by the area under the plasma concentration time curve, appeared to be unchanged in the presence of food.