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The bioavailabilities of flufenamic acid (I) from a commercial aluminum flufenamate (II) tablet and I capsule were estimated by measuring urinary excretion of I and its metabolites fluorometrically. The dissolution rates of I from both dosage forms were also determined. The effects of concomitant intake of food or antacid on the bioavailabilities from the II tablet and the I capsule were investigated. The extent on I bioavailability from the II tablet was less than 30% of that from the I capsule. Dissolution tests suggested that the low bioavailability of I from II tablet resulted from the extremely slow release of I from the II complex. Intake of a standard meal retarded I absorption from I capsule, but did not affect that from the II tablet. Ingestion of dried aluminum hydroxide gel granules had little effect on I bioavailability from the I capsule.

Ten patients who were scheduled for surgery due to an internal damage of the knee joint, were treated 2 days before operation 3 times daily with an ointment containing flufenamic acid (Mobilisin spezial). At the time of operation, plasma and synovial fluid, tissue samples from the synovial membrane, Hoffa's fat pad and-- as far as possible--meniscus and articular cartilage were taken. Until 72 h after the operation, urine samples were collected. The flufenamic acid level was determined by means of high pressure liquid chromatography associated with fluorometric detection. Flufenamic acid was detected in all tissues of the knee joint and in the synovial fluid. The highest concentration of flufenamic acid was found in the synovial membrane.

Etofenamate [2-(2-hydroxyethoxy)ethyl-N-(alpha, alpha, alpha-trifluoro-m-tolyl)-anthranilate] was administered to dogs by the oral route. Minor amounts of etofenamate (Eto) and its glucuronide were found in urine and feces. The main portion of metabolites was eliminated as flufenamic acid (Flu) and hydroxy derivatives of Eto and Flu. Furthermore, a highly lipophilic fraction was isolated (extraction and TLC) and further separated into several compounds (HPLC, GLC). These metabolites were identified as Eto oleate, palmitate, linoleate, stearate, palmitoleate, myristate, and laurate by NMR and MS. The structures were confirmed by comparison with authentic material. The conjugation of etofenamate with fatty acids is an example of a new route of drug metabolism.

Eight nonionic surface-active agents were each incorporated at a concentration of 10% into a white petrolatum ointment base containing 10% flufenamic acid with or without dimethyl sulfoxide. Percutaneous absorption was studied by determining the plasma concentration of flufenamic acid in New Zealand White rabbits at regular intervals for 8 hr following application of the ointment. The percutaneous absorption of flufenamic acid was significantly increased when sorbitan trioleate, polyoxyl 8 stearate, or polyoxyethylene 2 oleyl ether were added to the ointment containing flufenamic acid and white petrolatum. The percutaneous absorption of flufenamic acid was increased significantly when sorbitan monopalmitate, sorbitan trioleate, polyoxyl 8 stearate, polyoxyethylene 20 cetyl ether, or polyoxyethylene 2 oleyl ether were added to the ointment containing dimethylsulfoxide, flufenamic acid, and white petrolatum.

Etofenamate in biological specimen can be determined by gas-liquid chromatography with etofenamate benzyl ether as internal standard. Determination in urine is done directly after extraction and concentration, whereas plasma and homogenates from organs have to be prepurified by thin-layer chromatography. Unchanged etofenamate is found in small amounts in human urine (0--4, 6--6, 6--8 h p. appl.). Inflamed rat paws after local application contain up to 75 microgram etofenamate/g in comparison to only 2 microgram flufenamic acid/g tissue. Both compounds are also found in non-inflamed paws, contents being only 3--4% as compared to the inflamed tissue. Elimination of etofenamate from the inflamed area occurs with a half-life of approx. 8.5 h. These results from gas-liquid chromatography correspond to results from t.l.c./fluorescence measurements.

1-O-acyl glucuronides are reactive Phase II metabolites which can alkylate chemical nucleophiles. Industrial sulfate ester mixed anhydrides have been reported to be active acylating agents. This study was undertaken in order to establish that sulfate ester mixed anhydrides of clinically useful drugs could be synthesized, purified, and characterized as reactive chemical species. Their ability to alkylate 4-(p-nitrobenzyl)pyridine (NBP) and their stability in aqueous solution was compared with 1-O-acyl glucuronide conjugates of the same drugs. Synthesis of the 1-O-acyl glucuronides of the hypolipidemic agent, clofibric acid, and the nonsteroidal antiinflammatory drugs flufenamic acid and indomethacin were catalyzed by immobilized microsomal rabbit liver UDP-glucuronyltransferase. Potassium salts of the sulfate ester mixed anhydrides of these drugs were synthesized chemically by temperature-controlled reaction with chlorosulfonic acid in anhydrous pyridine. Half-lives at pH 2.0, 6.0, 7.4, and 10.0 were determined for each compound. The reactivity of the acyl glucuronides and sulfate ester mixed anhydrides towards the standard chemical nucleophile, 4-(p-nitrobenzyl pyridine (NBP), was measured using a spectrophotometric assay at several substrate concentrations. Acyl sulfate ester mixed anhydrides were shown to be 3-20 times more reactive towards NBP than their corresponding 1-O-acyl glucuronides. For both glucuronides and sulfate esters, relative reactivity towards NBP was: clofibric acid greater than indomethacin greater than flufenamic acid. This behavior paralleled the hydrolytic instability of the compounds.

Flufenamic acid (200 mg) was administered in the form of a soft capsule to 8 young healthy volunteers after an overnight fast. The drug was absorbed irregularly and plasma curves showed large variation. Peak plasma concentrations varied strongly (6-20 micrograms/ml) but were usually reached within 1.5 h. The terminal elimination half-life is long (5-22 h) and the total body clearance is low (80-150 ml/min) causing long mean residence time (4-28 h). The total apparent volume of distribution is much larger than the total body water volume. The large intersubject variations led to the conclusion that mean values of the pharmacokinetic parameters of flufenamic acid after oral administration are not useful for practical purposes.

The biological availability of flufenamic acid after oral administration of the drug in both hard and soft gelatin capsules was studied in dogs and humans. The soft gelatin capsules produced consistently higher plasma concentration-time curves.

The elimination of ionized urinary fluorine was studied in groups of eight subjects treated during several days with niflumic acid, flufenamic acid, sulindac, antrafenine and floctafenine. Sulindac and floctafenine do not changes this elimination. After administration of niflumic acid, flufenamic and antrafenine, the urinary elimination of ionized fluorine increase in all the subjects. This increase is manifested from the start of treatment and persists for several days after it has been stopped. The administration of three drugs also results in an elevated level of ionized plasmic fluorine the duration of treatment. The results prove the existence in the human organism of a metabolic process capable of effecting the ionization of the organic fluor contained in the drugs studied. This biotransformation causes a fluorine impregnation of endogenous origin that is permanent and relatively stable, and whose consequences are examined (risk of fluorine osteosis and possibility of therapeutic application).

In order to ascertain the mode of anti-inflammatory action of a topical non-steroidal anti-inflammatory drug, etofenamate which is a diethylene glycol ester of flufenamic acid, the in vitro test for the mechanism of the action were carried out. Etofenamate (3 microM) was hydrolysed to flufenamic acid at a rate of 39.5% and 57.0% of the dose during 30 and 60 min incubation, respectively, when incubated with rat peritoneal macrophages stimulated with starch and bacto peptone in phosphate-buffered saline. PGE2 generation by these cells in MEM medium was dose-relatedly inhibited with etofenamate as well as flufenamic acid at the dosage range of 1 to 30 microM. This suggests that unchanged etofenamate is active, since the highest conversion rate of etofenamate to flufenamic acid was 15% of the dose during the incubation. Etofenamate produced a dose-related inhibition against lipoxygenase prepared from peritoneal polymorphonuclear leucocytes of guinea pigs, and its activity (IC50 = 5.3 X 10(-5) M) was stronger than that of caffeic acid; flufenamic acid was inactive. Inhibitory activity of etofenamate was one-third or less that of flufenamic acid against the hypotonic-hyperthermic lysis of rat erythrocytes and heat-denaturation of bovine serum albumin. From these results, it was suggested that topically applied etofenamate produces its anti-inflammatory action through prostaglandin synthesis inhibition by flufenamic acid produced in the inflammatory tissue and inhibition of prostaglandin synthesis by macrophages and lipoxygenase inhibition by unchanged etofenamate.

Renal elimination of etofenamate was studied after oral (200--1200 mg/kg) and intravenous (75 mg/kg) application to dogs. Free flufenamic acid and total fenamates (except phenolic metabolites) were determined. In accordance with other N-arylanthranilic acid derivatives after etofenamate only small amounts are renally eliminated; these results are specific for dog and differ to other animal species. Renally eliminated amounts (up to 8%) are not dependent on dose, the i.v. results also being in the same range. Proportions of free flufenamic acid is small in comparison to total fenamates. Renal elimination occurs preferentially on the first day after application. Biliary elimination of etofenamate and its metabolites was investigated after intravenous as well as intragastric application. Intact etofenamate was found after i.v. and i.g. application, part of it being conjugated. Hydroxyderivatives of Etofenamate (eto) were identified: 5-OH-eto (i.v. and i.g.), 4'-OH-eto (i.v.) and the 5.4'-dihydroxy-eto (i.g.). A further eto-derivative found after i.v. application could not be characterized. Amounts of flufenamic acid (flu) and its hydroxyderivatives (esp. 5-OH-flu) were increased after hydrolytic degradation. These results show that metabolic degradation does not occur primarily be conversion to flufenamic acid; etofenamate itself is degraded by hydroxylation and/or conjugation and subsequent formation of the corresponding flufenamic derivatives.

N-(2-Methyl-3-chlorophenyl)anthranilic acid (tolfenamic acid) and its metabolites in serum and urine were analyzed by a reversed-phase ion-pair HPLC method. The major metabolites were N-(2-methyl-3-chloro-4-hydroxyphenyl)anthranilic acid, and one of the minor metabolites was N-(2-formyl-3-chlorophenyl)anthranilic acid, i.e., products resulting from hydroxylation in either the methyl group or the methylchlorophenyl group of tolfenamic acid, and further oxidation of the hydroxymethyl group to a formyl group.

When [14C]haloperidol decanoate, a long-acting neuroleptic and an ester of haloperidol and decanoic acid, was incubated in human whole blood and plasma and in rat plasma and homogenates of rat brain, lung, liver, kidney, pancreas and muscle, no hydrolysis of the ester was seen. Although the decanoate was hydrolyzed by partially purified carboxylesterase, addition of rat plasma or liver homogenate to the enzymic reaction mixture resulted in marked inhibition of hydrolysis, whereas addition of the defatted residues of plasma or liver produced only partial inhibition. The enzymic hydrolysis was inhibited also by beta-lipoprotein and albumin, depending on their concentrations. The assumption that interaction between haloperidol decanoate and protein resulted in inhibition of the hydrolytic reaction mediated by the enzyme was validated by kinetic models and experimental data. The kinetics were apparently competitive. Based on the kinetic analysis, the interaction between the decanoate and albumin or beta-lipoprotein was investigated by measuring their equilibrium constants and extent of protein binding. Haloperidol decanoate appeared to interact with several proteins; this was exemplified by other measures of protein binding, an increasing effect of proteins on the solubility, and the partition ratio of the ester. The interaction between haloperidol decanoate and proteins caused marked stabilization of this ester against enzymatic hydrolysis and, thereby, influenced its metabolism.

The fibrinolytic effect of diiodosalicylate was expressed as apparent units urokinase. The dissociation constant of the urokinase-inhibitor complex is increased 19 times in the presence of 10(-2) M diiodosalicylate. The binding of diiodosalicylate to the antiactivator was estimated and the increase in free urokinase in the presence of diiodosalicylate was calculated. With 10(-2) M diiodosalicylate present only 4% of the inhibitor remains free to bind urokinase. Therefore, the fibrinolytic action of diiodosalicylate can be explained on the basis of its binding to the inhibitor and the release of free urokinase.