Diclofenac In Plasma Research Articles

Femtomole analysis of diclofenac in human plasma by gas chromatography/negative ion chemical ionization/mass spectrometry using (18O2)diclofenac as internal standard

A stable isotope dilution gas chromatography/negative ion chemical ionization/mass spectrometry assay for diclofenac in human plasma is described. The preparation of (18O2)diclofenac and its use as an internal standard for quantitative gas chromatography/mass spectrometry is shown. A sample processing and derivatization sequence with product recovery of 84.7% was found. The method presented permits quantitative measurement of diclofenac in human plasma at the lower femtomole level. Plasma levels of diclofenac after administration of diclofenac gel were estimated.

Detection and quantification of non-steroidal anti-inflammatory agents by gas chromatography/mass spectrometry: diclofenac.

A sensitive and reliable gas chromatography/mass spectrometric assay for diclofenac in plasma using selected ion monitoring is described. The procedure is based on the acidic extraction of diclofenac and ketoprofen (internal standard) with toluene. Both compounds are converted into their ethyl ester derivatives with ethanol containing 0.5% (v/v) sulphuric acid. No internal cyclization to indolone side product is produced in these conditions. The ions monitored are m/z 214 for diclofenac and m/z 209 for ketoprofen. The main recovery of diclofenac added to plasma has been estimated around 84.6% (120 ng ml-1, n = 4). The intra-assay and inter-assay variability were 1.9% and 10.3%, respectively. The sensitivity was lower than 2 ng ml-1. The applicability of the assays to study the bioavailability of two formulations in a multiple-dosage trial is described. The method has been used in more than 600 determinations without any interference.

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.

Clinical investigation of sodium diclofenac sustained-release suppositories

Sustained release suppositories of sodium diclofenac (SR-Supp) were evaluated in 8 patients who were in pain. In terms of the study of plasma diclofenac concentration profiles in 4 healthy male humans, plasma diclofenac concentrations of more than 50 ng/ml were maintained for 8 h in one subject, for 9 h in another, and for more than 12 h in two others after administration of a Sr-Supp containing 50 mg sodium diclofenac. In the clinical investigations of SR-Supp, 8 patients having chronic rheumatoid arthritis with severe pain were treated with SR-Supp. Plasma diclofenac concentrations in patients were determined only at 4 h after administration of SR-Supp, but in all cases, they correlated well with the values obtained in healthy subjects. The effect of SR-Supp in alleviating pain was sustained for 10 h or more, and allowed the patients to sleep comfortably through the night.

A new metabolite of diclofenac sodium in human plasma.

1. Among the phenolic metabolites of diclofenac in human plasma, an unknown compound (metabolite VI) was detected by h.p.l.c. and g.c. methods. This was also found in baboon plasma. 2. Metabolite VI was identified as 3'-hydroxy-4'-methoxy diclofenac by mass and n.m.r. spectroscopic analysis. Comparison with synthetic reference compound confirmed its structure. 3. In plasma, metabolite VI persists much longer than do unchanged diclofenac and the other phenolic metabolites. In urine, metabolite VI and its conjugates are excreted in trace amounts only. 4. A synthetic sample of metabolite VI was shown to be virtually inactive in animal models of inflammation and pain.

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.

Investigation of sustained-release suppository of sodium diclofenac in humans

A sustained-release suppository of sodium diclofenac prepared with a mixed base of glyceride and natural soya lecithin sustained the plasma diclofenac concentrations significantly in human subjects, with a three-times slower apparent absorption rate (absorption half-life: 2.9 h) in comparison with that after administration of a commercial suppository of sodium diclofenac (absorption half-life; 0.9 h). The addition of a high-melting point glyceride or hydrogenated soya lecithin in the suppository caused a slower apparent absorption rate of diclofenac with an absorption half-life of 6.3 h. Dissolution of diclofenac from the sustained-release suppository used in this study may occur according to the apparent leaching type mechanism proposed by Higuchi; i.e. the permeating rate of rectal fluid into the suppository's matrix may regulate the release of diclofenac from the suppository.

Sustained-release of sodium diclofenac from suppository

The increased solubility of sodium diclofenac in a suppository base in the presence of lecithin resulted in a slow release of sodium diclofenac from the base. In a study using dogs, the administration of a sodium diclofenac suppository prepared from triglyceride and lecithin as bases (lecithin suppository) at a dose of 2 mg of the drug/kg dog weight maintained the plasma diclofenac concentration within an effective pharmacological range for relatively long periods without a transient high diclofenac concentration in the plasma. The bioavailability of diclofenac after administration of the suppository containing lecithin was equivalent to that observed following the administration of a conventional suppository prepared with only a triglyceride as the base. Rat rectal mucosal damage caused by sodium diclofenac was moderated by the administration of the lecithin suppository, probably due to the low concentration of sodium diclofenac in the rectal fluid due to a slow release of sodium diclofenac from the lecithin suppository.

Sensitive method for the determination of diclofenac in human plasma by gas chromatography-mass spectrometry

Sensitive method for the determination of diclofenac in human plasma by gas chromatography-mass spectrometry

The pharmacokinetics of diclofenac sodium following intravenous and oral administration.

The pharmacokinetics of diclofenac were examined following single rapid intravenous injection and also following single oral doses to healthy female volunteers. After intravenous injection plasma levels of diclofenac fell rapidly and were below the limits of detection at 5.5 h postdosing. Individual drug profiles were described by a triexponential function and mean half-lives of the three exponential phases were 0.05, 0.26 and 1.1 h. After oral doses of enteric-coated tablets, the lag time between dosing and the appearance of drug in plasma varied between 1.0 and 4.5 h. However once drug absorption had commenced similar plasma drug profiles were obtained in different individuals. Peak plasma diclofenac levels ranged from 1.4 to 3.0 microgram . ml-1. The mean terminal drug half-life in plasma was 1.8 h after oral doses. This value was not significantly greater than the value of 1.1 h following intravenous doses. Fifty percent of orally dosed diclofenac did not reach the systemic circulation due, predominantly, to first-pass metabolism.