Effect of pyrazinamide on the renal excretion of urate and on the bromsulfalein excretory function of the liver
Part 1. Effect of Pyrazinamide on the Urate Excretion in Man
The urate metabolism of the Korean was first studied following which the effect of various antituberculous drugs, especially of pyrazinamide (PZA), on the urate excretion were investigated. Subjects employed in this study included both normal and tuberculous (TB) patients. Results may be briefly summarized as follows :
A. In 14 male subjects, the normal plasma concentration of urate was on the average 4.3±0.1 mg% while the urinary output of urate was 460±55 mg/day. Similar values were also obtained in females as well as in TB patients who are treated with streptomycin (SM), paraaminosalicylic acid (PAS) or isonicotinic acid hydrazid (INH).
B. The plasma concentration of urate was markedly increased within 24 hours after the start of PZA administration. This elevation of plasma urate level was maintained as long as PZA was administered and was associated with the corresponding reduction in the urinary excretion of urate in absence of any change in both the inulin and PAH clearances.
C. This anti-uricosuric action of PZA was affected by neither metabolic acidosis nor alkalosis, which was induce either before or simultaneously with the administration of PZA.
D. Salicylate (3 mg/day), when administered with PZA, was able to counteract the appearance of hyperuricemia due to PZA. Moreover, salicylate was also toe relieve patients from the state of hyperuricemia which was brought about by the PZA treatment.
E. The administration of ACTH (30 units/day) relieved patients from the PZA-induced hyperuricemia while cortisone acetate (100 mg/day) was less effective.
F. The administration of PAH neither altered the urinary excretion of urate nor prevented the hyperuricemic effect of PZA.
G. The administration of diodrast increased the urinary excretion of urate and in addition, prevented the hyperuricemic effect of PZA.
H. The possible mode of action of PZA on the urate excretion was discussed.
Part 2. Effect of Pyrazinamide on the Plasma Urate Level of the Rabbit, the Chicken and the Dog.
In view of known species differences in renal handling of urate, the effect of PZA was investigated in various animals to see if this drug also modifies the plasma level of urate in rabbits, chickens or in dogs. In all species studied, PZA failed to after the plasma urate level, suggesting that this drug is not able to interfere with the urate transport system in the kidney of these animals. Histological studies of various organs in the rabbit showed that no pathological findings could be detected after the PZA administration for 6 weeks, although the kidney showed a slight degree of degenerative changes in the tubule. However, the observed changes in not so marked s to reach at any conclusion.
Part 3. Effect of Pyrazinamide on Bromsulfalein Excretory Function of the Liver.
Since PZA is known to be a hepatotoxic agent, its effect on the bromsulfalein (BSP) excretory function of the liver was investigated in 13 patients.
As a whole, 2 patients developed a marked retention of BSP after 4 and 16 weeks, respectively. The former patient already had an abnormal BSP excretory function while the latter was normal before the start of PZA administration.
When the PZA administration was discontinued, the BSP excretory function returned to almost normal in 8 weeks in the latter patient, but was still abnormal in the former even after 30 weeks. In general, there was no clear correlation between the
development of marked BSP retention and the BSP excretory function of the liver prior to the administration of PZA. Moreover, the development of BSP retention was not related to the amount of PZA administered.