CONCENTRATIONS AND EFFECTS OF ZOPICLONE ARE GREATLY REDUCED BY RIFAMPICIN

Aims The effects of rifampicin on the pharmacokinetics and pharmacodyn amics of zopiclone, a non-benzodiazepine hypnotic, were studied. Metho ds In a randomized, placebo-controlled cross-over study with two phase s, eight young healthy volunteers took either 600 mg rifampicin or pla cebo once daily for 5 days. On the 6th day, 10 mg zopiclone was admini stered orally. Plasma zopiclone concentrations and effects of zopiclon e were measured for 10 h. Results The total area under the plasma zopi clone concentration-time curve after rifampicin was 18.0% (95% CI 13.5 - 22.5%) of that after placebo (86.1 +/- 34.5 ng ml(-1) h vs 473 +/- 114 ng ml(-1) h (mean +/- s.d.); P < 0.001). Rifampicin decreased the peak plasma concentration of zopiclone from 76.9 +/- 27.2 ng ml(-1) to 22.5 +/- 6.0 ng ml(-1) (P < 0.001) and the half-life from 3.8 +/- 0.6 h to 2.3 +/- 0.9 h (P < 0.005). A significant (P < 0.02) reduction in the effects of zopiclone was seen in three of the five psychomotor te sts used (digit symbol substitution test, critical flicker fusion test and Maddox wing test) after rifampicin pretreatment. Conclusions The strong interaction of rifampicin with zopiclone is due to enhanced met abolism of zopiclone. Zopiclone may show a reduced hypnotic effect whe n used concomitantly with rifampicin or other potent inducers of CYP3A 4 such as phenytoin and carbamazepine.