MARKED ENHANCEMENT BY RIFAMPICIN AND LACK OF EFFECT OF ISONIAZID ON THE ELIMINATION OF QUININE IN MAN

The effect of rifampicin and isoniazid pretreatment on the pharmacokin etics of quinine after a single oral dose (600 mg quinine sulphate) wa s studied in nine healthy young Thai male volunteers using a three-way randomized crossover design. Subjects were studied over three 2 day p eriods, during which they received no pretreatment, or pretreatment wi th daily 600 mg p.o. rifampicin for 2 weeks, or isoniazid 300 mg p.o. daily for 1 week, prior to quinine administration. The mean (+/- s.d.) clearance (CL/F) of quinine coadministered with rifampicin (0.87 +/- 0.35 l h(-1) kg(-1)) was significantly greater than that of quinine al one (0.14 +/- 0.05 l h(-1) kg(-1)). The mean difference in clearance f rom the control treatment was 0.73 l h(-1) kg(-1), with 95% confidence interval (C.I.) of 0.48 to 0.98. The unbound clearance (CLu/F) of qui nine, which reflects the activity of the drug-metabolizing enzymes, wa s considerably greater (6.9-fold) in subjects when rifampicin was coad ministered with quinine than that of quinine alone (6.9 +/- 3.6 vs 1.0 +/- 0.5 l h(-1) kg(-1); the 95% C.I. for the mean difference was 3.3 to 8.5). The mean elimination half-life of quinine when coadministered with rifampicin (5.5 +/- 3.0 h) was significantly shorter than when q uinine was given alone (11.1 +/- 3.0 h; the 95% C.I. for the mean diff erence was -8.6 to -2.6). In contrast to rifampicin, pretreatment for 1 week with 300 mg oral isoniazid had no significant effects on the ph armacokinetics of quinine. These results indicate that rifampicin pret reatment caused a marked increase (6.2-fold) in the clearance of quini ne, possibly due to enzyme induction. The extent to which the eliminat ion of quinine is enhanced by the concomitant administration of rifamp icin is likely to have important clinical consequences. Although the c linical significance of these findings is unknown, they indicate the n eed for caution in the administration of quinine to patients who are c oncurrently taking rifampicin as an anti-tuberculosis medication.