[Contribution to the study on phenylbutazone-sulfamides. I. -- Phenylbutazone-sulfanilamide and phenylbutazone-sulfathiazol associations (author's transl)].
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Chemical Phenomena↗
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Interaction of phenylbutazone with racemic phenprocoumon and its enantiomers in rats.
The interaction of phenylbutazone with the enantiomers and racemic [3H]phenprocoumon was studied in male inbred Wistar-Lewis rats following a single i.v. dose of the three forms of phenprocoumon and chronic oral treatment with phenylbutazone (average plasma concentration of about 60 microgram/ml). Phenylbutazone augmented the anticoagulant effect of R(+), S(-), and R, S(+/-) phenprocoumon to a similar extent. The free fraction of drug in the plasma of the enantiomers and racemic phenprocoumon increased in the presence of phenylbutazone. However, the rate of elimination of total drug from plasma and liver and the distribution between liver and plasma of all three forms of phenprocoumon remained nearly unaffected by phenylbutazone. Thus there is no evidence for a stereoselective drug interaction between phenprocoumon and phenylbutazone. For racemic [oH]phenprocoumon it was possible to follow the kinetics of free drug in plasma and liver along with the time course of anticoagulant activity. In these studies, free drug concentrations in plasma and liver increased during treatment with phenylbutazone, but the elimination rate constant of free racemic phenprocoumon in plasma and liver remained essentially unchanged. Phenylbutazone markedly decreased the volume of distribution referenced to free drug and the clearance of free phenprocoumon (i.e., intrinsic metabolic clearance). Whereas the total (bound and unbound) drug concentration--effect relationship in plasma and liver was shifted to the left in rats treated with phenylbutazone, such shift was not seen in the free drug concentration--response relationship. In conclusion, the increase in the free concentration of phenprocoumon in plasma and liver and the concomitant decrease in the clearance of free drug are the mechanisms responsible for the marked and sustained enhancement of the anticoagulant effect which follows treatment with phenbutazone.
4-Hydroxycoumarins↗
Clinical pharmacokinetics of phenylbutazone.
More than 25 years after phenylbutazone was introduced as a non-steroidal anti-inflammatory agent, basic knowledge is still accumulating on its pharmacokinetics in man. Phenylbutazone is almost completely absorbed after oral administration. A large fraction of the drug in plasma is bound to proteins, and the drug has a small volume of distribution. Phenylbutazone is eliminated by metabolism, only 1% being excreted unchanged in the urine. Approximately 10% of a single dose of phenylbutazone is excreted in bile as metabolites. About 60% of the urinary metabolites have been identified. A novel type of drug metabolite in man, the C-glucuronide, is formed by direct coupling of the pyrazolidine ring of phenylbutazone to glucuronic acid via a C-C bond. Phenylbutazone is oxidised in a phenyl ring or in the side chain to hydroxylated metabolites, which may undergo subsequent O-glucuronidation. After a single dose, C-glucuronidation seems to be the dominant reaction, while oxidation becomes increasingly important after repeated administration. Due to different pharmacokinetic properties of the metabolites, the C-glucuronides are detected in highest concentrations in the urine, while the pharmacologically active compounds oxyphenbutazone and gamma-hydroxyphenbutazone predominate in plasma. The biological (elimination) half-life of phenylbutazone in man is long, with a mean of about 70 hours, and exhibits large interindividual and intraindividual variation. The interindividual variation is largely due to genetic factors. The intraindividual variation is dose and time dependent. In an individual there may be several critical dose levels where a change in the elimination kinetics takes place. Since there is no correlation between the plasma level and the clinical or toxic effects of phenylbutazone, there is at present no need for routine monitoring of plasma concentrations of the drug.
Age Factors↗
Influence of dietary protein on the anti-inflammatory and ulcerogenic effects and on the pharmacokinetics of phenylbutazone in rats.
Influence of dietary protein deficiency on the anti-inflammatory and ulcerogenic effects and on the kinetics of phenylbutazone was studied in male Sprague-Dawley rats fed ad libitum a 21% (control) or a 5% (low) protein diet for 3 weeks. A low protein diet fed to a decrease in body weight gain, plasma proteins, albumin, globulins, hepatic total and microsomal proteins and in cytochrome P-450. Phenylbutazone produced a greater ulcerogenic effect in rats fed a low protein diet than in control rats; its anti-inflammatory effect did not increase. Plasma t 1/2 of phenylbutazone was longer in protein-deficient rats than in control rats. Dietary protein deprivation led to a decrease in the plasma clearance and plasma protein binding of phenylbutazone but did not lead to a change in its bioavailability. No relationship between the severity of gastric ulceration and the concentration of phenylbutazone or oxyphenbutazone in the stomach tissue was found in any animal of the two groups. The increased susceptibility of protein-deficient rats to the ulcerogenic effect of phenylbutazone was reversible and was not observed when these animals were fed a control diet for 3 weeks. It is concluded that a dietary protein deficiency increases the ulcerogenic toxicity of phenylbutazone relative to its useful anti-inflammatory effects.
Animals↗
Phenylbutazone ionization kinetics.
Phenylbutazone has been associated with bioavailability problems and has shown nonclassical behavior in phase-transport studies. This nonclassical behavior has been attributed, in part, to the fact that phenylbutazone, as a carbon acid, undergoes noninstantaneous ionization kinetics. Instantaneous reaction is an assumption made in many diffusion-limited transport models involving a simultaneous ionization reaction. The ionization kinetics of phenylbutazone were determined at an ionic strength of 0.1 and 25 degrees using a stopped-flow spectrophotometer. A log kobs versus pH profile for the approach to the ionization equilibrium was determined, and a mechanism consistent with the profile was postulated. The percent enol versus the diketo form of phenylbutazone acid as well as pKaenol and pKadiketo was kinetically calculated. The protonation reaction was highly catalyzed by general acids while the deprotonation reaction was highly catalyzed by general bases. The general acid, water, was a poor proton donor to the anionic form (the so-called mesomericanion) of phenylbutazone.
Buffers↗
Elimination and serum protein binding of phenylbutazone in patients with renal insufficiency.
In uremic patients the serum protein binding of phenylbutazone was significantly decreased. The concentration of the dialyzable drug estimated by equilibrium dialysis was increased by 117-1100% (mean +/-SD = 502 +/- 236%). No correlation exists between the serum protein binding of phenylbutazone and the concentration of serum albumin, urea and creatinine. The serum protein binding of glymidine was also decreased in the uremic patients (dialyzable fraction increased by 214%). The apparent plasma levels of phenylbutazone immediately after its ingestion (600 mg per os) were decreased in uremic patients (44.5 +/- 11 mug/ml) in comparison with healthy subjects (66.3 +/- 17.3 mug/ml). The half life of phenylbutazone was decreased in the uremic patients (41.7 +/- 12.4 hr) in comparison with healthy volunteers (58.9 +/- 14.9 hr). It is suggested that the accelerated elimination of phenylbutazone in uremic patients is caused by an altered distribution of the drug caused by its decreased serum protein binding.
Adult↗
The biotransformation of phenylbutazone (Butazolidin).
In the present paper a review of published work on the metabolic fate of phenylbutazone is given, inclusive of results from very recent radiotracer studies in man. Phenylbutazone, 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine, being a highly lipophilic compound, is readily absorbed following oral administration to man, and is re-eliminated mostly in metabolized from via urine and faeces. In the biotransformation of phenylbutazone in the human organism two major pathways are involved, i.e. straightforward C-glucuronidation at the 4-position of the pyrazolidine ring and, to a much lesser extent, hydroxylation at one of the phenyl rings or at the n-butyl side chain. Hydrolytic cleavage of the amide bonds in the dioxopyrazolidine ring which, theoretically, would be a possible third pathway of biotransformation, does not take place to any significant extent. In contrast to man, the animal species studies, namely rat and dog, metabolize phenylbutazone predominantly through hydroxylation. This principal difference in metabolic handling may explain why the elimination rate of the drug from plasma is largely different in these species, the average half-lives being 3-4 hours in rat and dog as compared to about 80 hours in man following single doses. The enzyme systems that are primarily involved in phenylbutazone metabolism are mono-oxygenases in the animal species considered, and glucuronyltransferase in man. Auto-induction of enzymes, resultiing in an enhanced elimination of the drug from plasma in the course of repeated administration, has unequivocally been proven for rat and dog only but not for man.
Administration, Oral↗
Phenylbutazone inhibition of equine platelet function.
Nonsteroidal anti-inflammatory drugs impair platelet aggregation and secretion in man, pigs, and rabbits and inhibit platelet thromboxane/prostaglandin synthesis. The present investigation studied the effects of phenylbutazone on platelet aggregation and bleeding times in the horse. Aggregation responses to adenosine diphosphate and collagen were markedly impaired 15 minutes and 2 hours after treatment, but 4 hours after treatment, platelet responses approximated those prior to treatment. The in vivo effect of phenylbutazone correlated with its plasma concentrations. Phenylbutazone, like aspirin, appeared to exert its effect by inhibiting thromboxane/prostaglandin synthesis, because thrombin-induced malondialdehyde formation was inhibited. However, unlike aspirin, free arachidonate-induced malondialdehyde synthesis was reduced but not eliminated, which suggested that phenylbutazone may have more than one site of action. Although collagen-induced platelet aggregation was impaired, a response was still present, and bleeding times were not altered by phenylbutazone treatment. To account for these findings, it is proposed that equine platelets can respond to collagen by thromboxane/prostaglandin independent pathways. The physiologic and pathophysiologic importance of these findings is discussed.
Adenosine Diphosphate↗
Phenylbutazone-warfarin interaction in the dog.
The administration of phenylbutazone together with warfarin to dogs resulted in an elevation of the free fraction of warfarin in the plasma from 2-6 to 8-0% thus providing direct support for the notion that phenylbutazone induced inhibition of warfarin binding to plasma proteins. This inhibition as evaluated by a kinetic method was accompanied by a two-fold decrease in the plasma half-life of warfarin from 18-4 h in control animals to 9-6 h in phenylbutazone-treated animals. Marked increases in warfarin-induced hypoprothrombinaemia were observed when at doses up to 8 mg kg-1 (orally) it was given with phenylbutazone (50 mg kg-1, orally). The unbound fraction of warfarin in canine plasma ranged from 1-7 to 4-3% indicating individual differences in the extent of the plasma binding of warfarin in the dog.
Animals↗
Antiphlogistic action of phenylbutazone in normal and adrenalectomized rats of different ages relation to the 5-hydroxytryptamine blood concentration.
The authors have attempted to demonstrate the effect of bilateral adrenalectomy on carrageenin-induced oedema and on the antiphlogistic action of phenylbutazone in relation to the changes of blood 5-hydroxtryptamine (5-HT) in rats of different ages (21 days, 42 days, 3 months and 18 months old). It was found that the influence of adrenalectomy on the antiphlogistic action of phenylbutazone and on the blood 5-HT concentration is related to the age of rats. The lowest antiphlogistic action of phenylbutazone was found in 21-day-old rats and highest in the 18-month-old ones. In adrenalectomized 21- and 42-day-old rats the antiphlogistic action is decreased and fully suppressed in rats 3 and 18 months old. Adrenalectomy does not influenced basal values of blood 5-HT concentration. Blood 5-HT in adrenalectomized rats with inflammationadrenalectomized rats 42 days and 3 months old with inflammation after injection of phenylbutazone an increase of 5-HT was observed, but in 18-month-old animals in which antiphlogistic action is highest a decrease of 5-HT was observed.
Adrenalectomy↗
Correlations of DNA, RNA and protein levels in duodenal mucosa with antiinflammatory potency and disposition to gut damage of non-steroidal agents. Comparative behaviour of glucametacine, indometacin, phenylbutazone and ibuprofen.
As far as molar ratio is concerned, glucametacine was half as potent as indometacin, twice as active as phenylbutazone and four times more effective than ibuprofen in preventing cotton granuloma. Both indometacin and phenylbutazone induced dose related gastrointestinal ulcerations and increase of 51Cr tagged erythrocytes in feces. The former drug displayed gut toxicity at anti-inflammatory doses, the latter at doses approximately four times larger. Glucametacine was still devoid of damaging effects at a dose ten times larger than the minimal one capable of inhibiting granuloma growth. Ibuprofen, too, failed to induce ulcers at all doses examined; however, it displayed a trend toward gut bleeding when doses that increased blood corticosterone were attained. Studies on duodenal mucosa showed that in rats on cotton granuloma, DNA, proteins and DNA:RNA ratio increase as compared to unimplanted rats. Glucametacine and phenylbutazone reversed the increase of DNA and proteins, respectively. Indometacin decreased all forementioned constituents of duodenal mucosa while inducing haemorrhages and ulcers on gut. Furthermore, in naive rats, unlike glucametacine and phenylbutazone, indometacin induced a decrease in protein content of duodenal mucosa. Differences in disposition of gut toxicity among glucametacine and other anti-inflammatory drugs are discussed.
Animals↗
Benorylate interaction with indomethacin and phenylbutazone.
The simlutaneous oral administration of benorylate (4-(acetamido) phenyl 2-acetoxybenzoate) with either indomethacin or phenylbutazone to rats suffering from Freund's adjuvant-induced arthritis leads to an anti-inflammatory effect which is significantly greater than the effect of the same drugs administered alone. Such an additive anti-inflammatory effect is not apparent when the metabolites of benorylate (paracetamol, acetylsalicylic acid) are administered with indomethacin or phenylbutazone. Paracetamol does not increase the anti-inflammatory effect of indomethacin or phenylbutazone and acetylsalicylic acid clearly antagonizes it. The molecule of benorylate itsel is therefore responsible for the additive anti-inflammatory effect. However, if antipyretic activity (yeast-induced hyperthermia) is examined instead of anti-inflammatory activity, the simultaneous oral administration of the different drugs always produces an additive effect. It is concluded that the antagonism between indomethacin or phenylbutazone and non-steroidal anti-inflammatory drugs other than benorylate is present at some receptors but not all. The clinical implications of the results are discussed.
Animals↗
Mechanism of action of colchicine. III. Antiinflammatory effects of colchicine compared with phenylbutazone and indomethacin.
Colchicine suppresses the development of carrageenan-induced edema in the rat with a minimum effective oral dose of 6.0 mg/kg. The slope of the dose-response regression line for colchicine differs significantly from that of indomethacin and phenylbutazone. Based on the dosages required to achieve a 50% suppression of this inflammation, colchicine is 0.6 and 1.5 times as potent as indomethacin and phenylbutazone, respectively. In the reversed passive Arthus reaction in the rat, the suppressive activity of colchicine is at least 50 times that of indomethacin and 100 times that of phenylbutazone. The possible significance of these results with regard to the unique effectiveness of colchicine in the treatment of gout is discussed.
Animals↗
Effects of phenylbutazone, tolbutamide, and clofibric acid on binding of racemic warfarin and its enantiomers to human serum albumin.
The effect of phenylbutazone, tolbutamide, and clofibric acid on the binding of racemic warfarin and its enantiomers to human serum albumin was studied by equilibrium dialysis. Warfarin had one primary and two secondary binding sites on the albumin molecule. No difference in binding was detected at the primary binding site; the extent of R(+)-isomer binding at the secondary binding sites was 2.5 times greater than the corresponding S(-)-isomer binding. Phenylbutazone and warfarin appear to compete for the same primary binding site on the albumin molecule. Tolbutamide interferes with the binding of warfarin enantiomers at their secondary sites. Clofibric acid has a less pronounced effect on warfarin binding than does phenylbutazone or tolbutamide.
Binding, Competitive↗
Treatment of ankylosing spondylitis with flurbiprofen or phenylbutazone.
Flurbiprofen (150-200 mg daily) and phenylbutazone (300-400 mg daily) were compared in the management of 27 patients with active ankylosing spondylitis. This was a parallel, double-blind, and randomized trial of 6 weeks duration. Both drugs were equally effective in the relief of pain and tenderness of the affected joints. Overall subjective improvement, assessed by the patient and the investigator at the end of the trial, favored phenylbutazone, but it did not reach a statistically significant level. The mean values of the endpoint parameters of spinal motion showed statistically significant improvement in both groups, except in the Schober test in the flurbiprofen group and chest expansion in the phenylbutazone group. Untoward effects characteristic of these drugs were found in a few patients.
Clinical Trials as Topic↗
Phenylbutazone and the horse--a review.
The clinical uses and side-effects of phenylbutazone in man, horses, and other animals are reviewed. The blood dyscrasias commonly described in man have not been reported in the horse, although several of the more minor side-effects have occasionally been seen (e.g. water retention, depression, transient staggering and phlebitis). Despite the lack of documented evidence, the toxicity of phenylbutazone in the horse is considered to be lower than that in man. This may be associated with the lower dose rates normally used, the more rapid plasma clearance rate and the comparatively younger age of most horses under treatment. The following guidelines for the use of phenylbutazone in practice are put toward. It should only be used under strict veterinary control and then only if there are clear clinical indications. It should not be given if there are signs of gastro-intestinal ulceration, clotting defects or any cardiac, renal or hepatic dysfunction. Dose rates should be kept to a minimum and the drug withdrawn immediately if any side-effects occur or if there is no clinical response within 4 days. If prolonged therapy is necessary, periodic haematological analyses should be carried out.
Agranulocytosis↗
A double blind trial to assess the value of alclofenac compared with phenylbutazone in the management of rheumatoid arthritis.
A double-blind cross-over study using a double placebo technique was employed to compare the effectiveness of daily alclofenac 3 g and phenylbutazone 300 mg in rheumatoid arthritis. (2) Thirty-one patients with classical or definite rheumatoid arthritis entered the trial. Twenty-three patients completed the trial; eight patients were withdrawn while on alclofenac, six developing a rash and two having inadequate analgesia. (3) Relief of pain on both drugs was comparable. (4) When questioned at the end of the trial, sixteen patients preferred phenylbutazone, four preferred alclofenac. (5) No significant changes in laboratory values were found, apart from a slight mean fall in haemoglobin on phenylbutazone. (6) There were significantly more side effects on alclofenac and rashes were particularly prominent.
Adolescent↗
Diftalone: a new non-steroidal anti-inflammatory agent: comparative study with phenylbutazone in the treatment of rheumatoid arthritis.
A double-blind study was carried out to compare the effectiveness and tolerability of diftalone and phenylbutazone in thirty patients with classical or definite rheumatoid arthritis, randomly distributed between the two treatment groups. Both drugs were administered according to a progressively decreasing daily dosage schedule: 1,000 mg during the 1st week; 750 mg the 2nd week and 500 mg from the 3rd week on for diftalone; 400 mg, 300 mg, and 200 mg daily for the 1st, 2nd and from the 3rd week on respectively for phenylbutazone. The study lasted twelve weeks. The clinical controls and laboratory tests were performed weekly up to the 8th week, while the final evaluation was made at the end of the 3rd month. Twelve patients in the group receiving diftalone and fourteen in the phenylbutazone group completed the trial. Clinical improvement was observed in both groups. Effectiveness was somewhat more evident in the diftalone group. Tolerability was acceptable for both drugs, althoug the diftalone patients showed less frequent and intense side-effects than those treated with phyenylbutazone. No significant differences were found as regards the laboratory parameters, except a significant fall of the E.S.R. (less than 0-05) in the diftalone group. Diftalone seems to be an effective and safe anti-inflammatory agent in the treatment of rheumatoid arthritis.
Adult↗