Effect of pyrazinamide on rifampicin kinetics in patients with tuberculosis

Rifampicin and pyrazinamide constitute an important part of drug regimens advocated for tuberculosis therapy, along with INH and streptomycin/ethambutol. The International Union against Tuberculosis and Lung Disease has also suggested the inclusion of these two drugs as part of short course chemotherapy for tuberculosis. Hence this study was undertaken to evaluate the influence of pyrazinamide on rifampicin kinetics when the two are given together. In a randomized, cross-over, single dose study, 16 patients with untreated pulmonary tuberculosis, after an overnight fast, were administered either rifampicin 450 mg + INH 300 mg (study A) or rifampicin 450 mg + INH 300 mg+pyrazinamide 1500 mg (study B). Blood samples were collected for serum rifampicin estimation at 0, 0.5, 2, 4, 6 and 8 h. Various pharmacokinetic parameters (Cmax, Tmax, t1/2, Kel, area under plasma concentration time curve (AUC), Vd & Cpl of rifampicin) were calculated. It was observed that rifampicin concentration in study A in contrast to study B was significantly higher at 6 h (P < 0.01) and 8 h (P < 0.05), while there were no significant differences in serum rifampicin concentration at 0.5, 2 and 4 h. A significant difference was also observed in AUC and Cpl. In study A, AUC was higher (P < 0.05), while Cpl was lower (P < 0.02), than in study B. From the above data it appears that on concomitant administration of pyrazinamide in patients on rifampicin therapy, AUC of rifampicin is decreased while its clearance is increased.