The effects of inhibition and induction of the metabolism of buspirone on the plasma concentrations of 1-(2-pyrimidinyl)-piperazine (a piperazine metabolite), the principal active metabolite of buspirone, were investigated. Two separate randomized, placebo-controlled cross-over studies with two phases were carried out in healthy volunteers. In Study I, six subjects took itraconazole 200 mg daily or matched placebo orally for 4 days. On day 4, 10 mg buspirone was administered orally. In study II, six subjects took rifampicin 600 mg daily or matched placebo orally for 5 days. On day 6, 30 mg buspirone was administered orally. Buspirone and piperazine metabolite concentrations in plasma were determined by gas chromatography. Itraconazole decreased the mean AUC of the piperazine metabolite by 50% (P<0.05) and the Cmax by 57% (P<0.05) compared with placebo, whereas the mean AUC and Cmax of unchanged buspirone were increased 14.5-fold (P<0.05) and 10.5-fold (P<0.05), respectively, by itraconazole. Rifampicin had no significant effect on the AUC of the piperazine metabolite, but it increased the mean Cmax of the piperazine metabolite by 35% (P=0.08). The mean AUC and Cmax of parent buspirone were reduced by 91% (P<0.05) and 85% (P<0.05), respectively, by rifampicin. The mean ratio of the AUC of the piperazine metabolite to that of buspirone was decreased 34-fold (P<0.05) by itraconazole and increased 7.6-fold (P<0.05) by rifampicin. In conclusion, itraconazole and rifampicin caused only relatively minor changes in the plasma concentrations of the active piperazine metabolite of buspirone, although they had drastic effects on the concentrations of parent buspirone.