Absorption Of Diclofenac Research Articles

Pharmacokinetics of diclofenac in rat model of diabetes mellitus induced by alloxan or steptozotocin

The pharmacokinetics of diclofenac were compared after intravenous and oral administration at a dose of 5 mg/kg in a rat model of diabetes mellitus induced by alloxan (DMIA) or streptozotocin (DMIS), and their respective control rats. Diclofenac was reported to be metabolized via the hepatic microsomal cytochrome P450 (CYP) 2C11 in male rats. The expression and mRNA level of CYP2C11 decreased in rat models of DMIA and DMIS. Hence, the time-averaged nonrenal clearance (Clnr) of diclofenac was expected to be slower in a rat model of diabetes. As expected, after intravenous administration, the Clnr values of diclofenac were significantly slower in rat models of DMIA (11.3 versus 13.6 ml/min/kg) and DMIS (8.06 versus 15.2 ml/min/kg) than those in control rats. As a result, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) values were significantly greater in rat models of DMIA (435 versus 367 microg min/ml) and DMIS (540 versus 329 microg min/ml). However, after oral administration, the AUC from time zero to the last measured time, 12 h, in plasma (AUC0-12 h) values were comparable between the rat models of DMIA and DMIS and their control rats, and this could be due to changes in the first-pass effect of diclofenac and was not due to a decrease in the absorption of diclofenac in the rat models of diabetes.

Is topical treatment of osteoarthritis site-specific?

As Vivian McAlister notes, the study by Hui and associates[1][1] demonstrated some systemic absorption of diclofenac after topical application. However, the plasma level was only 11.8 (standard deviation [SD] 4.2) ng/mL, approximately 125 times below the level seen after ingestion of a 50-mg tablet

In vitro and in vivo comparison of two diclofenac sodium sustained release oral formulations

The aim of this study was to investigate the effect of formulation on the pharmacokinetics of diclofenac in two sustained release formulations (formulation A and Voltaren SR ®) after oral delivery. The dissolution of diclofenac from sustained release formulation was pH-dependent. While drug released from both formulations increased with increased pH, the release kinetics of these two formulations was different. The pharmacokinetic study was conducted in 12 healthy subjects administered with multiple doses of 100 mg of diclofenac in a crossover design. There was a significant difference in area under the plasma concentration–time curve [AUC(0–24)] and C max observed. The formulation with a reduced diffusion exponent with increased kinetic constant results in increased absorption of diclofenac in vivo. This study demonstrated the impact of release mechanism of the formulation on the absorption in vivo.

Formation of ion-pairs in aqueous solutions of diclofenac salts

In this work we studied the ability of the diclofenac anion to form ion-pairs in aqueous solution in the presence of organic and inorganic cations: ion-pairs have a polarity and hydrophobicity more suitable to the partition than each ion considered separately and can be extracted by a lipid phase. The cations considered were those of the organic bases diethylamine, diethanolamine, pyrrolidine, N-(2-hydroxyethyl) pyrrolidine and N-(2-hydroxyethyl) piperidine; the inorganic cations studied were Li +, Na +, K +, Rb +, Cs +. Related to each cation we determined the equilibrium constant ( K XD) for the ion-pair formation with the diclofenac anion in aqueous solution and the water/ n-octanol partition coefficient ( P XD) for each type of ion-pair formed. Among the alkali metal cations, only Li + shows some interaction with the diclofenac anion, in agreement with its physiological behaviour of increasing clearance during the administration of diclofenac. The influence of the ionic radius and desolvation enthalpy of the alkali metal cations on the ion-pair formation and partition was briefly discussed. Organic cations promote the formation of ion-pairs with the diclofenac anion better than the inorganic ones, and improve the partition of the ion-pair according to their hydrophobicity. The values of the equilibrium parameters for the formation and partition of ion-pairs are not high enough to allow the direct detection of their presence in the aqueous solution. Their formation can be appreciated in the presence of a lipid phase that continuously extracts the ion-pair. Extraction constants ( E XD= P XD· K XD) increase passing from inorganic to organic cations. This study could help to clarify the mechanism of the percutaneous absorption of diclofenac in the form of a salt, a route where the formation of ion-pairs appears to play an important role.

Bioavailability of diclofenac after intramuscular administration to rats with experimental spinal cord injury

Spinal cord injury (SCI) has been proposed to reduce drug bioavailability after intramuscular administration owing to an impairment in blood flow to paralyzed limbs. To test this hypothesis, we studied diclofenac bioavailability after intramuscular administration in rats with SCI. Female Sprague-Dawley rats were submitted to SCI at the T8 level by contusion and received a 10-mg/kg intramuscular diclofenac dose in the thigh of the right hind limb 24 h after injury. Blood samples were drawn, diclofenac concentration was determined by high-performance liquid chromatography, and whole-blood concentration against time curves were constructed. SCI did not result in a significant change in C max and T max, compared with sham-lesioned controls, suggesting that the rate of drug absorption was not altered. Half-life was prolonged, and therefore area under the curve was greater in SCI than in sham-lesioned animals. Therefore, 24 h after SCI at the T8 level, intramuscular diclofenac bioavailability was not impaired but was actually enhanced. Results suggest that the rate of intramuscular diclofenac absorption is not significantly altered, although its elimination is impaired, during the acute phase of SCI. It then appears that SCI-induced pharmacokinetic alterations are complex, the global bioavailability depending on the sum of SCI effects on absorption, distribution, and elimination. Systematic studies on SCI-induced alterations are thus required to provide information leading to a rational dosing regimen design for SCI patients.

In vitro cutaneous disposition of a topical diclofenac lotion in human skin: effect of a multi-dose regimen.

This study determines comparative bioavailability of diclofenac sodium lotion compared to an aqueous solution after topical application to viable human skin in vitro. In addition, the difference between a single dose and multiple doses (8 times) was also determined. An in vitro flow-through diffusion cell system was employed, using radiolabelled diclofenac sodium. Multiple doses of lotion (2 microl/cm2 and 5 microl/cm2) delivered a total of 40.1 +/- 17.6 microg and 85.6 micro 41.4 microg diclofenac, respectively, at 48 h, compared to only 9.4 +/- 2.9 microg and 35.7 +/- 19.0 microg absorbed after topical application of diclofenac as an aqueous solution (P < 0.05). A single dose study showed no statistical difference between diclofenac delivered in lotion or an aqueous solution. Over 48 h the total absorption from lotion was 10.2 +/- 6.7 microg and 26.2 +/- 17.6 microg (2 microl/cm2 and 5 microl/cm2, respectively), compared to 8.3 +/- 1.5 microg and 12.5 +/- 5.7 microg from an aqueous solution. Both single doses of lotion and aqueous diclofenac showed decreased diclofenac absorption into the receptor fluid between 12 and 24 h. However, when applied multiple times, absorption from lotion was continually increasing up to 48 h. The total dose accountability ranged from 76.8 +/- 8.2% to 110.6 +/- 15. 1% of the applied dose. Diclofenac lotion exhibited enhanced diclofenac percutaneous absorption rate through human skin (mass, flux and partition coefficient) when applied a multiple number of times and this enhanced absorption was maintained over 48 h. This suggests that a constituent of the lotion (DMSO) will enhance human skin absorption of diclofenac when used in a multi-dose regimen, but not after a single dose.

Clinical pharmacokinetics of diclofenac. Therapeutic insights and pitfalls.

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylacetic acid class. When given orally the absorption of diclofenac is rapid and complete. Diclofenac binds extensively to plasma albumin. The area under the plasma concentration-time curve (AUC) of diclofenac is proportional to the dose for oral doses between 25 to 150 mg. Substantial concentrations of drug are attained in synovial fluid, which is the proposed site of action for NSAIDs. Concentration-effect relationships have been established for total bound, unbound and synovial fluid diclofenac concentrations. Diclofenac is eliminated following biotransformation to glucoroconjugated and sulphate metabolites which are excreted in urine, very little drug is eliminated unchanged. The excretion of conjugates may be related to renal function. Conjugate accumulation occurs in end-stage renal disease; however, no accumulation is apparent upon comparison of young and elderly individuals. Dosage adjustments for the elderly, children or for patients with various disease states (such as hepatic disease or rheumatoid arthritis) may not be required. Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), lithium, digoxin, methotrexate, cyclosporin, cholestyramine and colestipol.

Short‐term sucralfate administration alters potassium diclofenac absorption in healthy male volunteers

Aims Since patients who regularly take NSAIDS may use sucralfate because of its cytoprotective properties, we examined the influence of this compound on the pharmacokmetics of diclofenac. Methods Potassium diclofenac (105 mg) was administered orally to eighteen healthy male volunteers with or without a 5‐day pre‐treatment with sucralfate (2000 mg twice daily). Blood samples were collected at intervals post‐dose and serum concentrations of diclofenac were determined by reverse‐phase h.p.1.c. Results Pre‐treatment with sucralfate significantly decreased both the AUC(0,8 h) [2265 ng h Ml−1 (geometric mean) (range 1815–2827)vs 1821 ng h ml−’(1295–2562)] and the Cmax [1135 ng ml−1 (geometric mean) (range 898–1436) vs 701 ng ml−1 (501–981)] with no significant delay in absorption [tmax 1.0 h (median) (range 0.5–2.0) vs 1.0 h (0.5‐4.0)l. Conclusions The short‐tern treatment of healthy male volunteers with sucralfate decreases potassium diclofenac bioavailability. These findings suggest that either an appropriate increase in the diclofenac intake or the use of another gastric mucosa protector must be adopted.

Development of Skin Stripping Technique to Evaluate In Vivo Percutaneous Absorption of Diclofenac. I. Effects of Skin Stripping Sequence, Occlusion Time, and Sites of Application

Development of Skin Stripping Technique to Evaluate In Vivo Percutaneous Absorption of Diclofenac. I. Effects of Skin Stripping Sequence, Occlusion Time, and Sites of Application

Development of Skin Stripping Technique to Evaluate In Vivo Percutaneous Absorption of Diclofenac. II. Correlation with In Vitro Drug Release and Application to Topical Bioavailability Determination

Development of Skin Stripping Technique to Evaluate In Vivo Percutaneous Absorption of Diclofenac. II. Correlation with In Vitro Drug Release and Application to Topical Bioavailability Determination

Pharmacokinetics and metabolism of diclofenac sodium in Yucatan miniature pigs.

The pig has been suggested as an animal model in biomedical research because of its physiological similarity to man. Therefore, the pharmacokinetics and metabolism of diclofenac sodium (Voltaren) were studied in four Yucatan minipigs after intravenous administration of 25 and 50 mg and oral administration of 50 mg in a solution of 50 mL buffer, 50 mL water, and 200 mL water, and the results compared to historical data in man. The absolute bioavailability after oral administration of 50 mL buffer, 50 mL water, and 200 mL water solutions were 107, 97, and 109%, respectively, compared to approximately 50% in man. The total plasma clearance in minipigs was fivefold slower than in humans (57 +/- 17 vs 252 +/- 54 mL/hr/kg). The plasma levels of the metabolites 4'-hydroxy, 5-hydroxy, 3'-hydroxy, 4',5-dihydroxy, and 3'-hydroxy-4'-methoxy diclofenac were considerably lower in minipigs than in man after both i.v. and oral administration. These results suggest slower metabolism and/or enterohepatic recirculation of the parent drug in minipigs. The volume of distribution of the central compartment was 40% less in humans than in pigs (39 vs 67 mL/kg). The terminal half-lives of the parent drug were similar in pigs (2.4 hr) and humans (1.8 hr). The rate of oral drug absorption increased in the order of 50 mL aqueous, 200 mL aqueous, and 50 mL buffered solutions (Ka = 0.52 +/- 0.11, 0.59 +/- 0.13, and 1.2 +/- 0.7 hr-1, respectively). These trends are similar in man and suggest that both buffering and intake volume can affect diclofenac absorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Press-coated tablets for the sequential pulsed administration of two different drugs

The most common risk connected with non-steroidal anti-inflammatory drugs (NSAIDs) oral administration is presented by their local irritation effects on the mucosa of the gastro-intestinal tract. To prevent NSAID-induced mucosal lesions and ulcer formation or exacerbation a new dosage form was designed for the administration in sequential pulses of a mucosal protective agent firstly and then NSAID. The active substances are formulated in a press-coated tablet in which the inner core contains sodium diclofenac and the outer shell sucralfate. The shell composition includes rapidly disintegrating agents for the prompt release of the mucosal protective agent. Diclofenac release from the core starts only when the outer layer has completely disintegrated. In vitro release of the anti-inflammatory drug is not influenced by the sucralfate delivery impulse. Preliminary in vivo studies confirm that the presence of sucralfate does not prevent diclofenac absorption from the GI tract.

Pharmacokinetics and bioavailability of diclofenac in the rat

Diclofenac sodium is a widely used drug with interesting absorption and disposition features when administered to laboratory animals. The present study was undertaken to assess the pharmacokinetics of the drug after iv and gastrointestinal dosing to rats. Renal excretion of unchanged drug was negligible, but biliary excretion of the drug (unchanged and conjugated) was detected in bile duct-cannulated rats; it accounted for 27.2 and 31.2% of the total dose following iv and intraduodenal administration, respectively. Most of the drug excreted in the bile was conjugated diclofenac; unchanged drug accounted for only 4.7 and 5.4% of total diclofenac excreted in the bile after iv and intraduodenal dosing, respectively. In normal animals, intestinal absorption of the drug excreted in the bile resulted in higher drug concentrations in plasma than those obtained in bile duct-cannulated rats, but only after 60 min of dosing. When administered directly into the duodenum, diclofenac absorption was extremely fast and the maximum plasma diclofenac concentration was reached within 2 min. After oral dosing, an early peak was also observed, but it was lower than that obtained after intraduodenal dosing: 71% diclofenac bioavailability was found in bile duct-cannulated rats intraduodenally dosed, whereas in normal animals dosed by mouth a bioavailability of 79% was obtained. In normal animals intraduodenally dosed, an apparent bioavailability of 106% was observed. All of these features, particularly the influence of enterohepatic circulation on drug bioavailability, are discussed.

The relative bioavailability of diclofenac with respect to time of administration.

The pharmacokinetics of diclofenac after a single oral dose (50 mg) were studied in 10 healthy adults on two occasions separated by 2 weeks, once in the morning (dose administered at 07.00 h) and once in the evening (dose at 19.00 h). Peak serum drug concentrations as well as the area under the drug concentration-time curve were significantly less during the night compared with the day (Cmax: 1886 +/- s.d 901 vs 2791 +/- 1565 ng ml-1 and AUC: 2807 +/- 1376 vs 3681 +/- 1986 ng ml-1 h). However, the time to reach peak concentration (tmax) and the half-life of diclofenac (t1/2) were not significantly different on the two occasions. We suggest that the extent of diclofenac absorption is slightly lower following administration in the evening compared with administration in the morning.

Percutaneous absorption of diclofenac in rats and humans: aqueous gel formulation

The rat dorsal percutaneous absorption of sodium diclofenac increased with an increase in sodium diclofenac concentration in an applied aqueous solution, but the bioavailability was poor. The addition of 10% w/w ethanol in the aqueous solution containing sodium diclofenac apparently increased the percutaneous absorption of diclofenac, which was performed by the increase in the sodium diclofenac concentration in the applied, solution rather than by an increase in dorsal skin permeability to diclofenac. The administration of sodium diclofenac in the aqueous gel formulation, which was prepared with hydrogenated soya phospholipid, increased the plasma diclofenac concentration in rat significantly. The formulation causing high diclofenac concentration in rat plasma also resulted in a large accumulation of diclofenac in the dorsal subcutaneous tissue. The dorsal percutaneous administration of sodium diclofenac in the aqueous gel form to healthy human subjects caused a gradual increase of plasma diclofenac concentration during the experimental period of 8 h. The relative bioavailability of sodium diclofenac in the gel form in one subject was about 7% of that after rectal administration of a commercial suppository of sodium diclofenac.

Rat percutaneous transport of diclofenac and influence of hydrogenated soya phospholipids.

Poor penetration of diclofenac through in vitro rat dorsal skin including subcutaneous tissue was observed. The poor penetration of diclofenac seemed to be predominantly due to the poor permeability of the stratum corneum. Hydrogenated soya phospholipids (phospholipid) in aqueous gel form increased the penetration of diclofenac in the in vitro study, by increasing diclofenac transport through the stratum corneum. In the in vivo percutaneous absorption of diclofenac, the presence of phospholipid in aqueous gel form increased both plasma diclofenac concentration and diclofenac accumulation in the dorsal skin tissue, including subcutaneous tissue. Since a marked accumulation of diclofenac in the subcutaneous tissue after application of the aqueous gel was observed both in vivo and in vitro, percutaneous application of diclofenac in the aqueous gel form, prepared with phospholipid, may be available for topical treatment rather than for systemic treatment.

The influence of food on the absorption of diclofenac after single and multiple oral doses.

A single dose of enteric-coated diclofenac sodium was taken fasting and immediately after a standard breakfast by twelve healthy volunteers. A considerable delay in the onset of absorption was observed, non-fasting, varying from 2.5 to 12 h compared with 1.5 to 2.75 h when fasting. Peak plasma concentrations were reduced after food but areas under plasma concentration-time curves were comparable. Six subjects then took part in a study involving single and repeated dosing under fasting and non-fasting conditions. As before, prolonged and variable delays were observed when the enteric-coated tablets were taken after food. On repeated dosing, maximum plasma concentrations were reached after 6 h non-fasting compared with 2.5 h fasting. Peak plasma levels were, however, similar.

The influence of food on the absorption of diclofenac as determined by the urinary excretion of the unchanged drug and its major metabolites during chronic administration.

Six healthy subjects took diclofenac as an enteric-coated preparation twice daily for 17 days under the following conditions: (i) fasting, (ii) 15 min before a meal, and (iii) immediately after a meal. Urine specimens were collected on two separate days of each regimen and diclofenac and its total monohydroxylated metabolites measured. Statistical analysis of the excretion of diclofenac and its metabolites showed that, during chronic administration, absorption was not significantly influenced by dosing before or after food. The absorption pattern after both these modes of administration was comparable to that obtained under fasting conditions.

Rectal delivery of antiinflammatory drugs. II. The influence of basic amino acid salts on rectal absorption of diclofenac.

Rectal absorption of diclofenac (DC) and its salts with sodium (DCNa), L-arginine (DC-Arg), L-lysine (DC-Lys), and L-histidine (DC-His) was studied in dogs, rabbits and rats. Plasma levels of unchanged DC were measured by high performance liquid chromatography. Both the bioavailability and the plasma peak level of DC-Lys were the largest among the salts studied. The bioavailability of DCNa on oral administration in terms of plasma levels of DC was observed to be much larger than after rectal administration of DC but it was of the same order as those of rectal administration of DCNa, DC-Arg, and DC-His. The extents of bioavailabilty in rabbits and in rats were similar, but considerably better than that in dogs. The irritative effects of DC salts on the rectal mucosa in rats were studied by gross and light microscopic examinations following the administration of suspensions in 1% methyl cellulose solution. DC-Arg showed the weakest irritation of the rectal mucosa, and the irritation caused by 20% suspension was equivalent to that of 5% suspension of DCNa. The protective effects of counter ions against the histological damage caused by DC to the rectal mucosa increased in the order or sodiumglysinegarginine. From these results, it appears that the basic amino acid salts of DC may be useful as rectal delivery preparations for clinical use.