THE EFFECT OF ERYTHROMYCIN ON THE CYP3A COMPONENT OF SERTINDOLE CLEARANCE IN HEALTHY-VOLUNTEERS

The effect of erythromycin on the pharmacokinetic disposition of oral sertindole, a new antipsychotic compound, was investigated. Ten subjec ts who completed the study received a single 4-mg dose of sertindole w ithout or with concomitant erythromycin 250 mg taken orally 4 times da ily. Coadministration of sertindole and erythromycin led to a 33% decr ease (P < 0.05) in mean (+/-SD) time to reach maximum plasma concentra tion (t(max)) value and a 15% elevation (P < 0.05) in the mean maximum plasma concentration (C-max) value of sertindole. The mean area under the concentration-time curve (AUC) value of sertindole did not change significantly in the presence of erythromycin (alone: 159 +/- 111 ng. hr/mL, in combination: 179 +/- 144 ng.hr/mL, P > 0.05). The presence o f erythromycin also significantly increased the dehydrosertindole C-ma x and AUC means by 16 % and 21 %, respectively, possibly due to inhibi tion of the CYP3A metabolic isozyme responsible for the elimination of this metabolite. The rate of absorption of sertindole and the rate of appearance of dehydrosertindole in the systemic circulation after a 4 -mg sertindole single dose were slightly enhanced by concomitant dosin g of erythromycin. In conclusion, there is a small but noticeable effe ct of erythromycin on the pharmacokinetic disposition of sertindole. T he effects are believed to have little clinical significance.