Interventions for Tuberculosis Control and Elimination 2002

Pharmacokinetics. After oral intake of 1500 mg of pyrazinamide, a peak
level of 25 to 30 mg/L is achieved after one to one and a half hours (figure
19). 181 Pyrazinamide has one of the best penetrations into cerebrospinal
fluid among the anti-tuberculosis medications. 312,313 About four per cent
of pyrazinamide is excreted unchanged in urine and about 30% as pyrazinoic
acid. 314 It is only slightly influenced by ingestion of antacids, but
with a fatty meal T max is delayed and C max slightly lowered, although these
effects are unlikely to bear clinical relevance. 315 Absorption of pyrazinamide
is not influenced by food intake.
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Figure 19. Pharmacokinetics of pyrazinamide in healthy volunteers. Reproduced
from 181 by the permission of the publisher ASM Press.
Dosage. The dosages of pyrazinamide have varied greatly since its introduction.
In early periods, the usual dosage was around 40 to 50 mg/kg
body weight 316,317 and up to eight grams were given per day. 310 Such
dosages frequently resulted in hepatotoxicity 317 and its early withdrawal
from chemotherapy regimens. The current recommendations are to give
25 mg/kg body weight per day. 8,13
Adverse drug events (table 4). The two major adverse drug events of pyrazinamide
are hepatotoxicity 115,120,200,310,317-324 and interference with the metabolism
of purine. The latter leads to decreased excretion and accumulation
of uric acid, occasionally accompanied by gout-like arthralgia. 310,325,326 The
suppressive effect of pyrazinoic acid on uric acid excretion is maximal for