The effect of rifampicin and pyrazinamide on isoniazid pharmacokinetics in rats

Tuberculosis chemotherapy involves combination of the drugs isoniazid (INH), rifampicin (RMP) and pyrazinamide (PYR) for a 6‐month period. The present work investigated the influence of RMP and PYR on the pharmacokinetic parameters of INH when groups of rats were pre‐treated for 21 days with INH alone or in combination with RMP and/or PYR, in the following amounts per kg body weight: INH 100 mg; INH 100 mg+RMP 100 mg; INH 100 mg+PYR 350 mg; INH 100 mg+PYR 350 mg+RMP 100 mg. It was found that the co‐administration of PYR caused an increase in the INH distribution volume (Vd/F), half‐life of elimination (t1/2β) and clearance (ClT/F), and a decrease in the area under curve 0 to 24 h (AUC). Co‐administration of RMP caused an increase in the ClT/F and a decrease in the AUC. The combination INH+PYR+RMP caused an increase in the ClT/F and a decrease in the AUC. These significant pharmacokinetic interactions between the tuberculostatic drugs might be related to differences in the therapeutic and toxic effects. Copyright © 2007 John Wiley & Sons, Ltd.