Phenazone, metabolism

Eichelbaum, M., Ochs, H. R., Roberts, G., Somogyi, A., Pharmacokinetics and metabolism of antipyrine (phenazone) after intravenous and oral administration, Drug Res. 1982, 32, 575-578. 

Bepridil increases the rate of clearance of phenazone (anti-pyrine) and might therefore be expected to enhance the rate of clearance of other drugs that are metabolized (19). 

The phenazone component of dichloralphenazone is an enzyme inducer and hastens the metabolism of phenytoin (3). 

Activation of the CYP450 enzyme system, demonstrated by an increase in the metabolism of phenazone (antipyr-ine), has been found in 30 HIV-positive drug abusers (24). This activating effect was demonstrated after 28 but not after 14 days of treatment with fusidic acid 500 mg/day, suggesting time dependency. 

Phenazone, commonly known as antipyrine, is still used therapeutically in some countries, although it is now used mainly as a marker of hepatic enzyme drug metabolizing activity. It is an old compound with little recent investigation, usually taken in combination with other analgesics, and an exact analysis of its adverse effects is impossible. Phenazone seems to have a low toxicity index, in correspondence with its weak anti-inflammatory effect. Allergic reactions are very rare (SEDA-6, 92) (SEDA-14, 92) (SEDA-16,108), but subjects undergoing the phenazone test should be informed of the potential risk. 

The half-life of phenazone (antipyrine) was prolonged and its metabolic clearance significantly reduced in proportion to the dose of piroxicam administered to healthy young volunteers (SEDA-16,113). 

Spironolactone has a weak enzyme-inducing effect and enhances the metabolic breakdown of phenazone (antipyrine) (SED-9, 358). 

Many of the chemical interactions with carbon disulfide appear to be related to loss of microsomal cytochrome P-450. Carbon disulfide suppresses the hepatic cytochrome P-450 microsomal enzyme system. Elimination of phenazone, a drug often used in the study of hepatic microsomal enzyme activity, is significantly and reversibly inhibited in rabbits exposed to 193 ppm carbon disulfide for 5 hours a day, 6 days a week, for 6 months (Orzechowska et al. 1984). It has been proposed that the active sulfur atoms released following carbon disulfide metabolism suppress the cytochrome P-450 enzymes, thus inhibiting detoxification of other drugs or chemicals. 

Orzechowska-Juzwenko K, Wronska-Nofer T, Wiela A, et al. 1985. Phenazone biotransformation as a maker of metabolic efficiency of the liver in rabbits chronically exposed to carbon disulfide. Naunyn Schmiedeberg Arch Pharmacol 330 R13. 

It has antipyretie aetions similar to those of phenazone but owing to the risk of agranulocytosis its use is discouraged and mostly abandoned. However, the gentisate has sometimes been used. Aminopyrine is often employed in drug metabolism studies. 

Chronic exposure to lindane and other chlorinated pesticides can slightly increase the rate of metabolism of phenazone (antipyrine) and phenylbutazone. 

The probable reason is that the phenobarbital increases the metabolism of these NSAIDs by the liver, thereby hastening their clearance. Phenazone is metabolised by mixed function oxidase enzymes in the liver, for which reason it is extensively used as a model drug for studying whether other drugs induce or inhibit liver enzymes. In one study phenobarbital caused about a 40% reduction thereby demonstrating that the liver enzymes were being stimulated to metabolise the phenazone more rapidly. The clinical importance of these interactions is uncertain (probably small) but be alert for any evidence of reduced NSAID effects if phenobarbital is added. 

The phenazone , (p.434) component of dichloralphenazone is a potent liver enzyme inducer, which increases the metabolism and clearance of the warfarin, thereby reducing its effects. The effects of the cloral hydrate , (p.396) component appear to be minimal. 

Phenazone is an enzyme inducer, which increases the metabolism and clearance of warfarin, thereby reducing its effects. ... 

The pharmacokinetics and metabolism of phenazone (largely used as an investigational marker drug of enzyme induction or inhibition) were studied in two groups of patients with prostate cancer before and after they took either bicalutamide 50 mg daily (7 patients) or 150 mg daily (11 patients) for 12 weeks. Small changes in the phenazone pharmacokinetics were found (half-life reduced by 16.3% with the 50 mg bicalutamide dos-... 

A study in 10 healthy subjects found that ticlopidine 250 mg twice daily for 3 weeks decreased the clearance of phenazone (a marker of enzyme inhibition or induction). The AUC increased by 14% and the half-life increased by 27%, suggesting that ticlopidine has some mild enzyme-inhibiting effects. This is consistent with the way ticlopidine appears to inhibit the metabolism of theophylline , (p.ll77), but so far no other drugs seem to be affected to a clinically important extent. 

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