Interactions of buspirone with itraconazole and rifampicin: Effects on thepharmacokinetics of the active 1-(2-pyrimidinyl)-piperazine metabolite of buspirone

The effects of inhibition and induction of the metabolism of buspirone on t he plasma concentrations of 1-(2-pyrimidinyl)-piperazine (a piperazine meta bolite), the principal active metabolite of buspirone, were investigated. T wo separate randomized, placebo-controlled cross-over studies with two phas es were carried out in healthy volunteers. In Study I, six subjects took it raconazole 200 mg daily or matched placebo orally for 4 days. On day 4, IO mg buspirone was administered orally. In study II, six subjects took rifamp icin 600 mg daily or matched placebo orally for 5 days. On day 6, 30 mg bus pirone was administered orally Buspirone and piperazine metabolite concentr ations in plasma were determined by gas chromatography. Itraconazole decrea sed the mean AUC of the piperazine metabolite by 50% (P < 0.05) and the C-m ax by 57% (P < 0.05) compared with placebo, whereas the mean AUC and C-max 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 effec t on the AUC of the piperazine metabolite, but it increased the mean C-max of the piperazine metabolite by 35% (P = 0.08). The mean AUC and C-max of p arent buspirone were reduced by 91%, (P < 0.05) and 85% (P < 0.05), respect ively 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 an d rifampicin caused only relatively minor changes in the plasma concentrati ons of the active piperazine metabolite of buspirone, although they had dra stic effects on the concentrations of parent buspirone.