The influence of phenylbutazone on the zinc level in serum and paw tissue of rats with adjuvant arthritis.

Our problem was, can phenylbutazone influence zinc level in serum and paw tissue and is there any relationship to its antiinflammatory effect? Phenylbutazone and zinc concentration were photometrically determined in serum and in homogenated paw tissue of rats injected with Freund's adjuvant. The course of total serum zinc level is opposite to the course of paw swelling whereas zinc content of paw tissue increases with swelling in the first phase of arthritis. Phenylbutazone increases serum zinc level, and the increase is highest if phenylbutazone is given daily. Phenylbutazone slightly decreases paw zinc level, especially 5 and 12 hrs after administration, but only in the first phase of arthritis. Pharmacokinetics of phenylbutazone in serum is unaffected in arthritic rats whereas phenylbutazone content of paws is increased in the first and second phase of arthritis. When given alone zinc and phenylbutazone accumulate in the inflamed tissue, perhaps, in their plasma protein bound form. Phenylbutazone inhibits inflammation and concomitantly decreases invasion of proteins and protein-bound zinc into the paw. Possibly phenylbutazone inhibits inflammation by inhibition of zinc-containing dehydrogenases since such enzymes are inhibited in vitro by phenylbutazone.

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.

Investigation of phenylbutazone in synovial fluid.

1. Phenylbutazone was measured in the synovial fluid of 15 patients and found to be present in appreciable amounts which were related to plasma levels. 2. 80% of fluid levels were between 55% and 80% of those in plasma. 3. There was some evidence that in very actively inflamed joints phenylbutazone levels were lower. 4. There was no relationship to plasma or synovial fluid protein levels. 5. Phenylbutazone was found in one patient's synovial fluid three weeks after stopping the drug.

[Liver metabolism of drugs (author's transl)]. / Leberstoffwechsel von Arzneimitteln

Even if all problems of liver metabolism have not yet been clarified, it is nevertheless established that medicaments induces enzymes in the hepatic cells which influence the metabolism of drugs. Because their effect is unspecific, these enzymes can catabolize many drugs with different structures. About 200 substances are known which induce such enzymes. Among them, for example, is phenobarbital. It is therefore used in the treatment of some forms of icterus with freee bilirubin and for Cushing's syndrome. But enzyme induction can also lead to acute intermittent porphyrias and distrubances of the phosphorus-calcium metabolism. Extreme catabolism of a drug can be caused by overinduction of enzymes due to the administration of several incompatible medicaments.

Elimination and distribution of phenylbutazone in rats during the course of adjuvant-induced arthritis.

The elimination and distribution of phenylbutazone after administration of a single intravenous dose of 25 mg/kg was investigated before and at different stages of adjuvant-induced arthritis in the same group of rats. In other groups which were studied concurrently, the cytochrome P-450 and b5 levels and ethylmorphine demethylation of liver microsomes were determined. Total plasma protein and albumin concentrations were monitored and the binding of phenylbutazone to plasma proteins was investigated. In the acute phase of adjuvant-induced arthritis, there was 1) a pronounced decrease in the elimination rate of phenylbutazone and 2) a marked increase in the apparent volume of distribution. The former could be explained by a reduced rate of hepatic biotransformation of phenylbutazone. A pronounced decrease in the microsomal cytochrome content and a slow rate of ethylmorphine demethylation is in agreement with this assumption. The latter appeared to be a result of the reduced binding capacity of the rat plasma due to the decrease in albumin concentration. The cytochrome content of liver microsomes and the plasma albumin concentration, however, were restored when arthritis reached its chronic phase. Consequently, an impairment of the elmination and distribution of phenylbutazone was no longer apparent.