Half-life Of Phenylbutazone Research Articles

Pharmacokinetics of phenylbutazone in camels

Abstract Objective To document disposition variables of phenylbutazone and its metabolite, oxyphenbutazone, in camels (Camelus dromedarius) after single IV bolus administration of phenylbutazone, with a view to making recommendation on avoiding violative residues in racing camels. Animals 6 healthy camels (4 males, 2 females), 5 to 7 years old, and weighing from 350 to 450 kg. Procedure Blood samples were collected at 0, 5, 10, 15, 45, and 60 minutes and at 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 26, 28, 30, 40, 48, 50, 53, and 60 hours after IV administration of 4.5 mg of phenylbutazone per kg of body weight. Urine was obtained in fractions during the entire blood sample collection period. Serum and urine phenylbutazone concentrations were measured by high-performance liquid chromatography; assay sensitivity was 100 ng/ml. Serum oxyphenbutazone concentration was measured by gas chromatography/mass spectrometry; assay sensitivity was 10 ng/ml. Results Disposition of phenylbutazone was best described by a two-compartment open model. Mean ± SEM elimination half-life was 13.44 ± 0.44 hours. Total body clearance was 12.63 ± 1.64 mg/kg/h. Renal clearance was between 0.3 and 0.4% of total body clearance. The elimination half-life of oxyphenbutazone was 23.9 ± 2.09 hours. Conclusions The elimination half-life and total body clearance of phenylbutazone in camels are intermediate between reported values in horses and cattle. Extrapolation of a dosage regimen from either species to camels is, therefore, not appropriate. Elimination of phenylbutazone in camels is mainly via metabolism. Owing to the long half-life of phenylbutazone and of oxyphenbutazone, and to the zero drug concentration regulation adopted by the racing commissioner in the United Arab Emirates, practicing veterinarians would be advised not to use phenylbutazone in camels for at least 7 days prior to racing. (Am J Vet Res 1997;58:636–640)

The bioavailability of phenylbutazone in the horse.

[phenyl-14C]-Phenylbutazone was administered to 2 horses p.o. and i.v. on separate occasions. Plasma levels and urinary and faecal elimination of 14C were monitored for up to 7 days after dosing. Phenylbutazone was rapidly and extensively absorbed after oral administration, and its bioavailability was 91% assessed by comparison of plasma AUCs of unchanged drug after p.o. and i.v. administration. The plasma elimination half-life of phenylbutazone was 9.7 h and this was independent of the route of administration. The pattern of elimination of phenylbutazone was independent of the route of administration, with 55% of the dose being found in the urine in 3 days and a further 39% in the faeces in 7 days. These data, which are the first reports of the absolute bioavailability and excretion pathways of phenylbutazone in the horse, are discussed in terms of their significance for the gastrointestinal toxicity of this drug.

Phenylbutazone in the horse: a review.

Phenylbutazone is an acidic, lipophilic, non-steroidal anti-inflammatory drug (NSAID). It is extensively metabolized in the horse. The metabolites so far identified, oxyphenbutazone, gamma-hydroxyoxyphenbutazone, account for some 25-30% of administered dose over 24 h. The plasma half-life of phenylbutazone and termination of its pharmacological action are determined primarily by its rate of hepatic metabolism. Phenylbutazone acts by inhibiting the cyclooxygenase enzyme system, which is responsible for synthesis of prostanoids such as PGE2. It appears to act on prostaglandin-H synthase and prostacyclin synthase, after conversion by prostaglandin-H synthase to reactive intermediates. It markedly reduces prostanoid-dependent swelling, edema, erythema, and hypersensitivity to pain in inflamed tissues. Its principal use in the horse is for treatment of soft tissue inflammation. Phenylbutazone is highly bound (greater than 98%) to plasma protein. After i.v. injection, blood levels decline with an elimination half-life of 3-10 h. The plasma kinetics of phenylbutazone may be dose dependent, with the plasma half-life increasing as the drug dosage level increases. Plasma residues of the drug at 24 h after a single i.v. dose of 2 g/450 kg average about 0.9 microgram/ml, but considerable variation occurs. If dosing is repeated, the plasma residue accumulates to give mean residual blood levels of approximately 4.5 microgram/ml on Day 5 after 4 days of dosing. Approximately similar blood levels are found after a combination of oral and i.v. dosing. Experiments on large numbers of horses in training have been undertaken to ascertain the population distributions of residual blood levels after such dosing schedules. Absorption of phenylbutazone from the gastrointestinal tract is influenced by the dose administered and the relationship of dosing to feeding. Access to hay can delay the time of peak plasma concentration to 18 h or longer. Under optimal conditions, the bioavailability of oral phenylbutazone is probably in the region of 70%. Paste preparations may be more slowly absorbed than other preparations and yield higher residual plasma levels at 24 h after dosing, but further controlled studies are required. Phenylbutazone is easily detected in the plasma and urine of horses but concentrations in saliva are low. It is quantitated for forensic purposes by HPLC. The variability of this method between laboratories is about +/- 25%. Increasing urinary pH increases the urinary concentration of phenylbutazone and its metabolites up to 200-fold.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of oral cimetidine on plasma concentrations of phenylbutazone in horses.

Phenylbutazone was administered to six Thoroughbred horses in a cross-over study in which the horses received cimetidine pretreatment or no cimetidine pretreatment. Blood samples were collected at various times for 48 h after phenylbutazone administration and the plasma was analysed for phenylbutazone. Cimetidine pretreatment elevated phenylbutazone plasma concentrations during the first 8 h after phenylbutazone administration. The absorption rate, maximum phenylbutazone plasma concentrations and AUC were significantly greater with cimetidine pretreatment. The half-life of phenylbutazone did not change with cimetidine pretreatment; however, lower plasma concentrations of the metabolite gamma-hydroxyphenylbutazone were observed with cimetidine pretreatments. Plasma concentrations of the metabolite oxyphenbutazone were unchanged with cimetidine pretreatment compared to control values. Twenty-four-hour plasma concentrations of phenylbutazone were not different from control values with cimetidine pretreatment. This study suggests that concurrent treatment with cimetidine and phenylbutazone 24 h before race time does not result in elevations of plasma phenylbutazone concentrations above control values.

Effect of activated charcoal on absorption and elimination of phenobarbitone, carbamazepine and phenylbutazone in man.

The effect of activated charcoal, given as a water suspension, on the absorption and elimination of phenobarbitone 200 mg, carbamazepine 400 mg and phenylbutazone 200 mg, was studied in five healthy volunteers, using a randomized crossover design. Absorption of the drugs was almost completely prevented (more than 95%) when charcoal 50 g was ingested within five minutes of taking the drugs. When activated charcoal was taken one hour after the drugs, the mean inhibition of drug absorption was considerably less and the inhibition was greatly dependent on the individual rate of absorption. The half-life of phenobarbitone was markedly shortened from a control value of 110±23 h to 19.8±1.0 h (P<0.05), with a corresponding increase in plasma clearance from 4.6 ml/min to 23 ml/min, when activated charcoal 118 g, in five divided doses was given between 10 and 48 h after ingestion of the drug. The half-life of carbamazepine was shortened by 45% (P<0.05) and the reduction in the half-life of phenylbutazone (30%) by charcoal, too, was statistically significant. The only side effect from use of the charcoal suspension was constipation, which occured in three subjects after repeated doses, and which was easily treated with lactulose if required. Although activated charcoal should be given as soon as possible, even its delayed use may be indicated, due to the slow absorption often seen in acute intoxication. The use of multiple doses of charcoal appears to be indicated as an additional treatment of certain severe intoxications to prevent the release of drugs from charcoal, and to increase their rate of elimination if they are secreted into the gut with subsequent reabsorption.

Lack of correlation between induction of adjuvant arthritis and changes in metabolism and disposition of phenylbutazone in rats.

Phenylbutazone disposition after intravenous injection of 50 mg/kg was studied in Lewis and AVN rats treated by mycobacterial adjuvant in comparison with untreated animals. Although the arthritic lesions, body weight loss and decline in albumin concentration developed only in the Lewis strain, an increase of the extrapolated volume of distribution, decline in total body clearance and prolongation of the biological half-life of phenylbutazone were found in both strains of rats. Also the content of cytochromes P-450 and b5 was reduced in both Lewis and AVN rats.

The biological fate of 4-butyl-4-(beta-carboxypropionyloxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione (suxibuzone), antiinflammatory drug. II. The biological fate of suxibuzone (SB) after daily oral administration (author's transl)

The biological fate of 4-butyl-4-(β-carboxypropionyloxymethyl)-1, 2-diphenyl-3, 5-pyrazolidinedione : suxibuzone (SB) was studied in rats and beagle dogs. Furthermore, the effects of SB on liver microsomal drug metabolizing enzyme systems in rats were compared with those of phenylbutazone (PB), after daily oral administration of SB or PB for 1 week. 1) The biological fate of SB was different in rats and dogs and in the former a sex difference was noted. 2) Liver microsomal drug metabolizing enzyme systems were induced especially in male. 3) No difference between the two drugs was noted. However, when a single oral dose of SB was administered, keeping the PB schedule the same as above, the plasma half-life of PB was markedly shortened and maximum plasma levels of metabolites were rapidly reached. These results suggest that the biological fate of SB was stimulated by the enhancement or induction of liver microsomal drug metabolizing enzyme systems due to PB and its metabolites after daily oral administration.

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.

Impaired metabolic handling of drugs in rats with arthritis induced by 6-sulfonanilamidoindazole

A possible explanation for the previously reported “synergistic toxicity” of normally non-lethal doses of anti-inflammatory drugs in rats with arthritis induced by 6-sulfonanilamidoindazole (SAI) was sought by examining the drug-metabolizing capability of these arthritic rats. Rats given SAI had prolonged (10-fold) sleeping times when challenged with pentobarbital. The apparent plasma half-life of phenylbutazone was increased from 4.2 to 17.4 hr in SAI-treated rats. The mean “steady state” plasma concentration of phenylbutazone was two to three times higher in SAI-treated rats. The N-demethylation of aminopyrine in vitro by liver 9000 g supernatant enzyme preparations proceeded at a rate of approximately 25 per cent that of control rats. The results suggest that SAI-treated rats are defective in their drug-metabolizing capability.

Effect of oral contraceptives on plasma clearance

The effects of chronic steroid contraceptive therapy on drug clearance from plasma were studied by using plasma antipyrine, phenylbutazone, and cholecalciferol half-lives in women. After 3 mo of oral steroid therapy (Norinyl, 2 mg; norethindrone + mestranol), the antipyrine half-life was increased in 3 of 6 subjects, phenylbutazone half-life was not consistently altered, and vitamin D3 half-life was increased in 3 of 4 patients. After 1 to 7 yr of oral steroid theraphy, the antipyrine half-life was longer while taking the contraceptive than when the contraceptive treatment was discontinued in 4 of 6 subjects, whereas that of phenylbutazone was not consistently altered.

Drug metabolism in normal children, lead-poisoned children, and normal adults.

Drug-metabolizing capacities were determined in 10 normal adults and 10 children in the age range from 1 to 8 years. Among the latter, 2 were normal and 8 had biochemical evidence of lead poisoning but no clinical expression of plumbism. There were no differences between the 2 normal children and the 8 lead-poisoned children in their capacities to metabolize two test drugs, antipyrine and phenylbutazone. The mean antipyrine half-life in the whole group of 10 children, 6.63 hr, was significantly lower than the mean half-life of 13.58 obtained in adults. The mean phenylbutazone half-lives in the children and adults, 1.68 and 3.16 days, respectively, also differed significantly. Thus children in the age range studied appear to metabolize drugs at almost twice the rate of adults which differs from findings in animals in which drug-metabolizing capacities increase with maturation. In two other children who showed clinical as well as biochemical manifestations of acute plumbism, antipyrine half-lives were signficantly longer than normal and therapy with EDTA led to restitution toward normal.

Decreased plasma half-life of phenylbutazone in workers exposed to chlorinated pesticides

The plasma half-life of a single oral dose of phenylbutazone was investigated in 14 men occupationally exposed to a mixture of insecticides, mainly lindane, and in 12 matched controls with significantly lower plasma levels of lindane. — The mean plasma half-life of phenylbutazone was significantly shorter (p<0.05) in the subjects exposed to lindane than in the non-exposed controls, but there was no relationship between the half-life of phenylbutazone and the plasma level of lindane. No correlation was found between the plasma half-life of phenylbutazone and that of antipyrine determined in the same subjects two years previously. If the plasma half-life of phenylbutazone is accepted as an index of the metabolism of this drug, then the shorter half-lives found in the exposed subjects suggest that the metabolism of this compound can be enhanced by such environmental factors as exposure to chlorinated insecticides.

Changes in human drug metabolism after long-term exposure to hypnotics.

The influence of the newer, non-barbiturate hypnotics Mandrax (diphenhydramine-methaqualone) and nitrazepam on drug-metabolizing capacity was assessed and compared with the effect of amylobarbitone, a known inducer of drug-metabolizing enzymes. Plasma antipyrine and phenylbutazone half-lives and urinary output of 6beta-hydroxycortisol were used as indices. Volunteer subjects were exposed to therapeutic amounts of these agents and, in the case of Mandrax and barbiturates, further studies were carried out in dependent patients.Mandrax but not nitrazepam increased the rate of drug metabolism, presumably by enzyme induction. The degree of induction was comparable with that produced by hypnotic doses of amylobarbitone. The Mandrax-dependent and barbiturate-dependent patients were the fastest metabolizers studied. It is concluded that drug interactions resulting from interference with drug metabolism are as likely to occur with Mandrax as with barbiturates. On the other hand, it is unlikely that such drug interactions would occur with nitrazepam.

Anti-inflammatory and pharmacokinetic properties of sudoxicam N-(2-thiazolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

Sudoxicam has demonstrated potent anti-inflammatory and antipyretic activity in several laboratory animal models of inflammation, in the range 0·5–3 times that of indomethacin. The plasma half-life ranged between 8 hr (monkey), 13 hr (rat), 60 hr (dog) and 24–96 hr (man). Sudoxicam, combining the high potency of indomethacin with the extended plasma half-life of phenylbutazone, has been well tolerated by animals and man, and evaluation in human inflammatory diseases is proceeding.

Genetic control of phenylbutazone metabolism in man.

The purposes of the present investigation were to assess the genetic contribution to thevariability between individuals in the rate at which they metabolize phenylbutazone and to characterize the type of inheritance that controls the metabolism of the drug. The 155 persons investigated included 43 unrelated random individual subjects and the members of 28 two-generation family units. None of these subjects had taken drugs in the six months preceding the experiments. Each subject ingested an oral dose of phenylbutazone and the plasma half-life of the drug was determined. These non-pretreated plasma phenylbutazone half-lives suggest the existence of polygenic control, but the value of the data is marred by the frequency distribution being very skewed.The 142 persons given a second test, included 41 unrelated random subjects and 24 two-generation family units. A three-day course of oral phenobarbitone was followed by an oral dose of phenylbutazone and the plasma half-life of the latter determined. The phenobarbitone was given with the aim of "inducing" drugmetabolizing enzymes in the liver, thus rendering the environment more uniform. When the post-phenobarbitone half-lives were adjusted to a standard height they were approximately normally distributed. There was a significant regression of mean offspring value on mid-parent value, indicating that about 65% of the observed phenotypic variance of post-phenobarbitone plasma phenylbutazone half-lives is due to the additive effects of genes.Phenylbutazone metabolism in man is thus shown to be under polygenic control, and genetically controlled in a similar manner and to a similar degree to body height.Improved understanding of phenylbutazone metabolism may lead to improved therapeutic efficacy and a lower incidence of adverse reactions.

Effect of intensive occupational exposure to DDT on phenylbutazone and cortisol metabolism in human subjects.

The effect of intensive occupational exposure to DDT on drug and steroid metabolism was studied. The concentration of DDT‐related substances in the serum and fat of DDT factory workers was 20 to 30 times that in a control population. The serum half‐life of phenylbutazone was 19 per cent lower (p &lt; 0.01) and the urinary excretion of 6ß‐ hydroxycortisol was 57 per cent higher (p &lt; 0.01) in the DDT factory workers. There were considerable variations in the phenylbutazone half‐life in different people, and there were also individual differences in the urinary excretion of 6ß‐hydroxycOrfisol. The variability in these parameters found in the DDT factory workers or in the control population was, however, not correlated with the concentration of DDT in the serum. Although we do not know whether DDT storage in the general population is sufficient to increase phenylbutazone metabolism or the urinary excretion of 6B‐hydroxycOrfisol, our results suggest that the extent of possible changes in these parameters would be small.

Studies of the interaction of phenylbutazone, oxyphenbutazone and methandrostenolone in man.

SummaryThe action of methandrostenolone on phenylbutazone and its major metabolite, oxyphenbutazone, has been studied in man by determining the half-life and plateau plasma levels of the antirheumatic drugs. The anabolic steroid caused an increase in the plasma level of oxyphenbutazone, confirming previous studies. This effect was previously attributed to a change in volume of distribution. In the present study, in addition to the effect on volume of distribution, a prolongation of half-life of oxyphenbutazone was observed in one subject. In contrast, in six patients receiving continuous therapy with phenylbutazone, plasma levels were unchanged when methandrostenolone was superimposed. The plasma levels of oxyphenbutazone, determined in the same samples, were unaffected. The half-life of phenylbutazone in two patients was not changed upon the administration of methandrostenolone, showing that no alteration had occurred in the metabolism of phenylbutazone. Equilibrium dialysis experiments indicated competi...

Genetic control of drug levels in man: phenylbutazone.

Phenylbutazone was administered to seven pairs of identical (monozygotic) twins and to seven pairs of fraternal (dizygotic) twins. Individual half-lives ranged from 1.2 to 7.3 days. Subjects with identical genotypes (monozygotic twins) exhibited very similar phenylbutazone half-lives; significantly greater differences in half-life occurred in dizygotic twins. The previously established large variations among individuals in phenylbutazone metabolism appear to be genetically, rather than environmentally, determined.