PLASMA BUSPIRONE CONCENTRATIONS ARE GREATLY INCREASED BY ERYTHROMYCINAND ITRACONAZOLE

Background: The oral bioavailability of buspirone is very low as a res ult of extensive first-pass metabolism. Erythromycin and itraconazole are potent inhibitors of CYP3A4, and they increase plasma concentratio ns and effects of certain drugs, for example, oral midazolam and triaz olam. The possible interactions of buspirone with erythromycin and itr aconazole have not been studied before. Methods: The pharmacokinetics and pharmacodynamics of buspirone were investigated in a randomized, d ouble-blind, double-dummy crossover study with three phases. Eight you ng healthy volunteers took either 1.5 gm/day erythromycin, 200 mg/day itraconazole, or placebo orally for 4 days. On day 4, 10 mg buspirone was administered orally. Timed blood samples were collected up to 18 h ours, and the effects of buspirone were measured with four psychomotor tests up to 8 hours. Results: Erythromycin and itraconazole increased the mean area under the plasma concentration-time curve from time zer o to infinity [AUC(0-infinity)] of buspirone about sixfold (p < 0.05) and 19-fold (p < 0.01), respectively, compared with placebo. The mean peak plasma concentration (C-max) of buspirone was increased about fiv efold (p < 0.01) and 13-fold (p < 0.01) by erythromycin and itraconazo le, respectively. These interactions were evident in each subject, alt hough a striking interindividual variability in the extent of both int eractions was observed. The elimination half-life of buspirone did not seem to be prolonged by either erythromycin or itraconazole. The effe ct of itraconazole on the C-max and AUC(0-infinity) of buspirone was s ignificantly (p < 0.01) greater than that of erythromycin. The greatly elevated plasma buspirone concentrations resulted in increased (p < 0 .05) pharmacodynamic effects (as measured by the Digit Symbol Substitu tion test and the Critical Flicker Fusion test) and in side effects of buspirone. Conclusions: Both erythromycin and itraconazole greatly in creased plasma buspirone concentrations, obviously by inhibiting its C YP3A4-mediated first-pass metabolism. These pharmacokinetic interactio ns were accompanied by impairment of psychomotor performance and side effects of buspirone. The dose of buspirone should be greatly reduced during concomitant treatment with erythromycin, itraconazole, or other potent inhibitors of CYP3A4.