The in vitro metabolic inversion of R(-) to S(+) indoprofen.

The paper reports a study on the metabolic inversion of indoprofen (2-[4-(2-isoindolinyl-1-one)-phenyl]-propionic acid) following incubation of the drug with liver microsomes from non-induced and phenobarbital-induced rats. The enantiomeric composition of the drug was determined after different incubation times of the racemate and the individual isomers. The S(+)/R(-) ratio was evaluated by densitometry following HPTLC separation of the R(+)-1-phenylethylamides. After incubation of the racemate and the individual isomers, no detectable amounts of indoprofen catabolites were extracted from the acidified incubation mixture. An appreciable enrichment in the S(+) enantiomer was observed after incubation of both racemate and R(-)-indoprofen; the S(+)/R(-) ratio reached a maximum after 1 h. Values were higher in the case of induction. After incubation of S(+)-indoprofen, a small but statistically significant decrease of the S(+)/R(-) ratio was observed. The increase of the S(+)-isomer concentration observed following incubation of R(-)-indoprofen can be ascribed to metabolic inversion by phenobarbital-inducible liver enzymes.

Pharmacokinetic profile of indoprofen in elderly subjects.

Multiple dosing four times daily for 7 days of indoprofen 200 mg, a non-steroidal anti-inflammatory drug with a short half-life (t1/2), revealed drug accumulation in eight elderly subjects. This indicates a substantially longer t1/2 (11 h) than that reported in young persons (3 h). A reduction in dose compared to younger subjects is recommended in elderly patients with osteoarthritis.

Pharmacokinetics of indoprofen in elderly patients following repeated oral administration.

Twenty patients suffering from osteoarthritis or rheumatoid arthritis, aged between 60 and 85 years, received 200 mg indoprofen tablets thrice daily for 4-7 days. Following the last dose, plasma samples were drawn and analysed for indoprofen. The mean peak plasma concentration of 25.5 +/- 7.06 micrograms/ml indoprofen was reached after 1.25 +/- 0.71 h. The total area under the curve was calculated as 207.2 +/- 108.7 micrograms X h/ml. Indoprofen was eliminated with a mean elimination half-life of t1/2 beta = 8.29 +/- 2.93 h compared with 5.5 +/- 0.64 h in young subjects. In elderly patients receiving indoprofen, terminal plasma half-lives and area under the plasma level time curves corrected for body weight were moderately increased compared with young subjects whereas no significant differences were found for Vd beta. During the dosage interval indoprofen levels were appreciably higher in elderly patients than in healthy volunteers due to higher nadir values and slower elimination half-lives, whereas only minor differences could be detected for peak plasma levels. The differences observed between young healthy volunteers and elderly patients may be explained by the reduction of renal function with increasing age, since creatinine clearance was 30-40% lower than normal values. The dose schedule for elderly patients over 60 years of age should therefore be adjusted to 200 mg indoprofen twice daily. A further reduction of the total daily dose should be considered for patients suffering from renal diseases associated with reduced creatinine clearance.

Pharmacokinetics of the enantiomers of indoprofen in man.

Indoprofen, a non-steroidal analgesic and antiinflammatory drug whose activity and safety in man have been established in a large number of studies, has an asymmetric carbon atom and can therefore occur as either the (+) or the (-) enantiomer. As it has been shown that its pharmacological effects are almost entirely due to the (+) isomer (d-indoprofen), some pharmacokinetic properties of the latter have been studied in man in comparison with the racemic mixture given by oral administration, d-indoprofen is cleared from plasma and excreted in urine (as unchanged plus conjugated drug) at a slower rate than l-indoprofen. Moreover, no stereospecific inversion of d-indoprofen to the inactive enantiomer occurs after either single or repeated (one week) administration. The pharmacokinetic behaviour of d-indoprofen in the human organism appears to be the same after administration of the racemic form or of the dextro-enantiomer, when the latter is given at half the dose.

Some novel observations of a drug (indoprofen)--albumin interaction.

Indoprofen, a new-steroidal anti-inflammatory agent, binds to human serum albumin in an endothermic reaction at low degrees of saturation and with an exothermic reaction at higher drug to protein ratios. Although indoprofen appears to bind to the same primary site as diazepam, dialysis studies show an increased binding of both drugs in the presence of the other. This novel observation is probably due to the effect of the drugs on the N leads to B conformational change of human serum albumin.

Intra-articular drug therapy in rheumatoid arthritis. A study with indoprofen.

Six patients (4 men, 2 women) with moderate/large knee effusions due to rheumatoid arthritis (RA) were studied after receiving indoprofen, 25 mg intra-articularly and then 200 mg orally 1 week later. There was significant improvement in pain (t = 3.74, P less than 0.05), morning stiffness (t = 2.91, P less than 0.05) and range of movement (t = 2.52, P less than 0.05) for at least 1 week following the intra-articular injection. The terminal phase plasma half-life after the 200 mg oral dose was 6.4 +/- 0.7 h (mean +/- SEM) and was significantly longer than the often quoted plasma half-life of 2-3 h from previous studies, but much less than the pharmacodynamic half-life. Synovial fluid concentration were not significantly different from those in plasma in the post-distribution phase. Intra-articular indoprofen may be a useful addition to the treatment of RA.

How frequently should anti-inflammatory drugs be given? A study with indoprofen.

Indoprofen, despite its relatively short plasma half-life, was just as effective given twice daily as when the same daily total was given in four divided doses. There was a trend in favour of the twice daily regime for changes in morning pain and the duration of morning stiffness. Preferences were equally divided between the two regimes and efficacy was the usual reason for patients preferring one or other. Side-effects were no more frequent with the twice daily regime. Pharmacokinetics are no substitute for clinical experiment in planning the dosage regime of a non-steroidal anti-inflammatory drug.

Human pharmacokinetics of indoprofen.

The pharmacokinetics of indoprofen were investigated in several studies in healthy volunteers and in rheumatoid arthritis patients. In healthy subjects the drug is rapidly eliminated with a biological half-life of 2.3 h. The drug and its metabolites are almost completely excreted in urine within 24 h from administration. The absorption of indoprofen administered orally to fasting subjects as 100 mg capsules and 200 mg tablets is rapid and complete. The bioavailability of indoprofen tablets is not adversely affected by the presence of food in the gastrointestinal tract. Following administration of 600 mg of indoprofen per day for 7 days, no changes are observed in the drug plasma level profile. There are no substantial differences between healthy subjects and rheumatoid arthritis patients as regards the pharmacokinetics properties of oral indoprofen.

Kinetics of indoprofen in patients with renal insufficiency (a preliminary report).

Plasma and urinary indoprofen concentrations were determined by liquid chromatography in healthy subjects and two patients with reduced glomerular filtration rate (GFR) of about 25 ml/min. The plasma half-life of the drug was prolonged in renal insufficiency. Until further studies have been performed indoprofen should be used with care in patients with renal impairment. Tentatively, the size of the dose or interval should be adjusted in proportion to the estimated preserved GFR.

Interaction of glipizide and indoprofen.

The possible kinetic and dynamic interactions of indoprofen and glipizide were investigated in 6 healthy volunteers, taking indoprofen 200 mg t.i.d. for 7 days and a single dose of glipizide 5 mg before and during indoprofen medication. Series of blood samples were obtained for measurements of indoprofen, glipizide and glucose concentrations in blood. In addition urine concentrations of indoprofen were determined. The concentrations of indoprofen and glipizide were examined by HPLC and that of glucose enzymatically. Results suggest that indoprofen may reduce glipizide concentrations in plasma, but this does not seem to influence the blood glucose response to glipizide.

Plasma and synovial fluid pharmacokinetics and prostaglandin inhibitory effect of indoprofen in patients with rheumatoid arthritis.

Indoprofen was given intravenously (bolus followed by infusion) and orally to 7 patients suffering from active rheumatoid arthritis with knee joint effusion. Indoprofen readily penetrated into synovial fluid in amounts which were directly correlated with areas under curves of plasma drug levels. Synovial fluid acted as a compartment distinct from the central (plasma) compartment. Indoprofen caused a substantial decrease in E2 and F2 alpha prostaglandin concentration in synovial fluid.

Pharmacokinetics and metabolism of indoprofen in the hamster.

2-[p-(1-Oxo-2-isoindolinyl)phenyl]propionic acid (indoprofen) is rapidly absorbed after oral administration (2 mg/kg) to male and female hamsters. Peak plasma levels of about 12-13 microgram/ml are reached within 1 h of dosing. Plasma concentrations in males and females are similar until 4 h but different at subsequent observation times. The half-life of indoprofen in plasma is approximately 7 h for males and 16 h for females. In experiments with 14C-labelled compound, radioactivity is mainly excreted in the urine: 94% of the dose in 6 days for males and 73% in 5 days for females. The females also excrete a significant amount of the drug (22%) in the faeces, probably via the bile. Residual radioactivity in female carcasses on the 5th day represents 1% of the dose. The main excretory product is the unchanged drug as such (about 35% and 21%, respectively, in 0-24 hour urine for males and females) and as glucuronic acid conjugate (29% and 12%). Small amounts of 5- and 6-hydroxy-isoindolinyl derivatives, and of two metabolites whose structures have not been identified, are also found in the urine of the animals of both sexes.

Tissue distribution of 14C-indoprofen in the rat.

The tissue distribution of 14C-labelled 2-[p-(1-oxo-2-isoindolinyl)phenyl)propionic acid (indoprofen) after i.v. injection was studied in male and pregnant rats by whole-body autoradiography. Distribution was characterized by a rapid localization in the liver, kidneys and lungs. A significant amount of radioactivity found in the intestinal contents suggested biliary excretion. There was no indication of retention of the drug in the brain. In pregnant rats, radioactivity crossed the blood-placenta barrier to a moderate extent and low concentrations were found in foetuses.

Kinetics of analgesic response in man; an example with two non-steroidal anti-inflammatory analgesic drugs.

A double-blind, controlled trial is described in which a total of forty hospital in-patients suffering from severe post-operative pain were randomly allocated to treatment with one of two non-steroidal anti-inflammatory drugs, namely, either indoprofen which has a short half-life (two-hours) or naproxen which has a long half-life (thirteen hours). The drugs were administered orally on a single-dose basis. The doses used in this way were 300 mg of indoprofen or 250 mg of naproxen. Patients scored the severity of their pain on a five-point scale and these scores were recorded prior to and at fixed time intervals up to eight hours following administration of medication. No significant differences emerged between the two test drugs and the duration of the response was also found to be similar for the two compounds despite their very different plasma half-life values.