Metabolism Of Phenylbutazone Research Articles

Phenylbutazone Oxidation via Cu,Zn-SOD Peroxidase Activity: An EPR Study.

We investigated the effect of Cu,Zn-superoxide dismutase (Cu,Zn-SOD)-peroxidase activity on the oxidation of the nonsteroidal anti-inflammatory drug phenylbutazone (PBZ). We utilized electron paramagnetic resonance (EPR) spectroscopy to detect free radical intermediates of PBZ, UV-vis spectrophotometry to monitor PBZ oxidation, oxygen analysis to determine the involvement of C-centered radicals, and LC/MS to determine the resulting metabolites. Using EPR spectroscopy and spin-trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), we found that the spin adduct of CO3(•-) (DMPO/(•)OH) was attenuated with increasing PBZ concentrations. The resulting PBZ radical, which was assigned as a carbon-centered radical based on computer simulation of hyperfine splitting constants, was trapped by both DMPO and MNP spin traps. Similar to Cu,Zn-SOD-peroxidase activity, an identical PBZ carbon-centered radical was also detected with the presence of both myeloperoxidase (MPO/H2O2) and horseradish peroxidase (HRP/H2O2). Oxygen analysis revealed depletion in oxygen levels when PBZ was oxidized by SOD peroxidase-activity, further supporting carbon radical formation. In addition, UV-vis spectra showed that the λmax for PBZ (λ = 260 nm) declined in intensity and shifted to a new peak that was similar to the spectrum for 4-hydroxy-PBZ when oxidized by Cu,Zn-SOD-peroxidase activity. LC/MS evidence supported the formation of 4-hydroxy-PBZ when compared to that of a standard, and 4-hydroperoxy-PBZ was also detected in significant yield. These findings together indicate that the carbonate radical, a product of SOD peroxidase activity, appears to play a role in PBZ metabolism. Interestingly, these results are similar to findings from heme peroxidase enzymes, and the context of this metabolic pathway is discussed in terms of a mechanism for PBZ-induced toxicity.

In vitro and in vivo studies of the metabolism of phenylbutazone in the alloxan rat and rabbit.

In vitro and in vivo studies of the metabolism of phenylbutazone in the alloxan rat and rabbit.

Abnormal Metabolism of Phenylbutazone after Overdosage

Abnormal Metabolism of Phenylbutazone after Overdosage

Drug Metabolism by Leukocytes and Its Role in Drug-Induced Lupus and Other Idiosyncratic Drug Reactions

This review presents a unifying hypothesis that provides a connection between several types of hypersensitivity reactions associated with several types of drugs and explains some of the therapeutic effects (antiinflammatory activity and antithyroid effects) of these same drugs. This hypothesis centers on the oxidation of these drugs to chemically reactive metabolites by peroxidases. The drugs of interest have functional groups that are easily oxidized. The major peroxidase involved in this hypothesis is MPO because of its critical location in leukocytes which play a key role in the function of the immune system. However, thyroid peroxidase can probably also oxidize many of the same drugs to reactive metabolites, and this may be responsible for the thyroid autoimmunity observed in connection with some hypersensitivity reactions. Peroxidases have also been described in the skin and in platelets, and their presence may be responsible for the high incidence of skin reactions in the hypersensitivity response and the occurrence of immune-mediated thrombocytopenia, respectively. Involvement of other peroxidases, such as prostaglandin peroxidase, may also be important for antiinflammatory effects of drugs. In addition, leukocytes contain prostaglandin synthetase, and the activation of leukocytes leads to the release of arachidonic acid and the production of prostaglandins. This process may also lead to the metabolism of drugs to reactive metabolites. In studies of the metabolism of procainamide and dapsone, aspirin and indomethacin did not inhibit the formation of the hydroxylamine by neutrophils and mononuclear leukocytes. This is evidence against the involvement of prostaglandin synthetase in these oxidation; however, preliminary studies with other drugs suggest that prostaglandin synthetase may contribute to the metabolism of some drugs by leukocytes. Furthermore, the metabolism of phenylbutazone, phenytoin, and tenoxicam, as well as our preliminary work with other drugs such as carbamazepine, suggests that the range of drugs that are metabolized to reactive metabolites by peroxidases may be broader than initially suspected. There are several other drugs that do not fit into the functional group classes covered in this review but have similar properties. A good example is alpha-methyldopa, which is associated with drug-induced lupus, immune-mediated hemolytic anemia, and other hypersensitivity reactions. Such drugs may also be metabolized to reactive metabolites by peroxidases. Another aspect of the hypothesis is that an infection, or other inflammatory condition, may be an important risk factor for a hypersensitivity reaction because such a stimulus leads to activation of leukocytes which can lead to formation of reactive metabolites from certain drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Metabolism of phenylbutazone in rats.

The metabolism of phenylbutazone has been investigated in female rats dosed with the drug by gavage. The major route of excretion is via the urine; 50% of the dose being excreted in the first 24 h. A small percentage of the dose is excreted in the faeces. Following administration of 14C-phenylbutazone, five labelled, unconjugated hydroxy compounds were identified in the urine by t.l.c. and autoradiography; both hydrolysable and non-hydrolysable conjugates were found. Aqueous extracts of faeces contained O conjugates of oxyphenbutazone and 4-hydroxy-oxyphenbutazone (which may be a decomposition product). Urine metabolites soluble in organic solvents were quantified by inverse isotope dilution assay and spectrophotometric analysis. The major metabolite is the gamma-hydroxy derivative of phenylbutazone present both as the lactone and as the straight-chain compound, while oxyphenbutazone and p, gamma-dihydroxyphenylbutazone are minor metabolites.

Oxidative drug metabolism and inducibility by phenobarbital in sickle cell anemia.

The plasma elimination rates of antipyrine and phenylbutazone were studied in 8 patients with sickle cell anemia. The mean antipyrine half‐life (t½) in plasma was not significantly different in the sickle cell patients ( 12.0 ± 3.0 hr) than in a control group of 20 normal subjects (12.7 ± 0.9 hr). For phenylbutazone the mean tV2 was shorter in the sickle cell patients (2.1 ± 0.1 days) than in normal subjects (3.3 ± 0.2 days, p < 0.001); both mean apparent volume of distribution (aVD) and mean metabolic clearance rate (MCR) for this drug were significantly higher in the sickle cell group, which suggests increased extravascular distribution as well as more rapid hepatic metabolism. After administration of phenobarbital (2 to 3 mg/kg daily for 2 wk) consistent increases in rates of antipyrine and phenylbutazone metabolism were observed in 6 sickle cell anemia patients, which were comparable to those observed in 5 normal subjects. Two other patients who were taking drugs (methyltestosterone, isoniazid) known to alter cytochrome P‐450 function did not respond typically. Our results suggest that cytochrome P‐450 function and sensitivity to phenobarbital induction are unimpaired in most sickle cell anemia patients. Since uptake of heme into hepatocytes is probably increased in this disorder, this suggests that an adapative response develops during long‐term hemolysis such that heme biosynthesis and formation of microsomal cytochromes are not repressed.

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, l,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 form 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 studied, 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, resulting 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.

The influence of allopurinol and size of dose on the metabolism of phenylbutazone in patients with gout.

Administration of allopurinol 300 mg/day produced minimal changes in the disappearance of phenylbutazone in each of five subjects following single doses (6 mg/kg) in clinical range and caused some prolongation (21%, 52%) of drug half-lives in two of six subjects after single small doses (0.5 mg/kg); mean half-life was not significantly altered by allopurinol at either dose level (means of 52 versus 48 at 0.5 mg/kg and 68 versus 70 h at 6 mg/kg). Size of dose altered half-life when phenylbutazone was used alone; three subjects showed considerably longer half-lives at the higher dose (86 versus 47, 91 versus 41, 65 versus 38 h). Allopurinol caused a greater than 50% prolongation of half-lives in two of five subjects who received single 0.5 g doses of probenecid. These preliminary data do not indicate a need to change the dose of phenylbutazone when subjects are receiving allopurinol.

The metabolism of phenylbutazone in the rat.

1. After administration of [14C]phenylbutazone by stomach tube to rats 1/3 of the radioactivity was excreted in the faeces and almost 2/3 in the urine over 48 h. Biliary excretion after intraperitoneal injection was slightly more than 1/3 of the dose in 24 h.2. Major urinary metabolites were the side-chain oxidized metabolite II and a novel metabolite, III, which is oxidized both in a phenyl group and in the butyl side-chain. Only small amounts of oxyphenbutazone, unchanged phenyl-butazone and conjugates were found in the urine.3. Analysis of bile and plasma and experiments with an isolated perfused rat liver indicate that oxyphenbutazone is also an important metabolite. This compound is further metabolized to metabolite III which, like oxyphenbutazone, can be conjugated with glucuronic acid before excretion.4. The concentration of the highly protein-bound oxyphenbutazone exceeded that of the more readily formed metabolite II in the plasma of the intact animal 6 h after giving phenylbutazone.5. It is concluded that phenylbutazone is extensively metabolized by oxidation in the rat. The γ-carbon in the butyl side-chain is the preferred site of oxidation, followed by the para position in one of the phenyl groups. Pharmacokinetic factors such as differences in the degree of protein binding favour the renal excretion of the side-chain oxidized metabolites.

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.

Studies on the combination of drugs. IV. Effect of 4-hydroxyantipyrine and N-acetyl-p-aminophenol on the metabolism of phenylbutazone, oxyphenbutazone and ketophenylbutazone

When 4-hydroxyantipyrine (HOAT), being the metabolites of aminopyriine and antipyrine, was used together with anti-inflammatory medicinals of pyrazolidione series, the metabolisms of the phenylbutazone (Bu) and ketophenylbutazone (KBu) were suppressed by the liver slices of rabbits and rats, but no influence of hydroxyphenylbutazone (OBu) was recognized on the metabolism. When N-acetyl-p-aminophenol (NAPAP) was used together, the metabolisms of Bu and KBu were suppressed in rat liver slices and no influence of OBu was observed. With rabbit liver slices, any influence of the joint use was not recognized. The metabolism of Bu in rat liver slices, to which either HOAT or antipyrine were administered continuoulsy in advance, was not so different from that of normal liver, and neither suppressive nor promoting phenomenon were observed. The blood concentration of Bu and KBu in rabbits is maintained by joint use of HOAT, and OBu has shown any significant differences when used alone. Jointly using the NAPAP, the blood concentration of KBu was simply maintained.