title: The effect of erythromycin on the CYP3A component of sertindole clearance in healthy volunteers.
abstract: The effect of erythromycin on the pharmacokinetic disposition of oral sertindole, a new antipsychotic compound, was investigated. Ten subjects who completed the study received a single 4-mg dose of sertindole without or with concomitant erythromycin 250 mg taken orally 4 times daily. Coadministration of sertindole and erythromycin led to a 33% decrease (P < 0.05) in mean (+/- SD) time to reach maximum plasma concentration (tmax) value and a 15% elevation (P < 0.05) in the mean maximum plasma concentration (Cmax) 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 of erythromycin also significantly increased the dehydrosertindole Cmax and AUC means by 16% and 21%, respectively, possibly due to inhibition 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 dosing of erythromycin. In conclusion, there is a small but noticeable effect of erythromycin on the pharmacokinetic disposition of sertindole. The effects are believed to have little clinical significance.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Wong
authors.forename: G
authors.initials: G
authors.lastname: Cao
authors.forename: R J
authors.initials: RJ
authors.lastname: Mack
authors.forename: G R
authors.initials: GR
authors.lastname: Granneman
mesh_terms: D000284:Administration, Oral; D000328:Adult; D014150:Antipsychotic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D004917:Erythromycin / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D007211:Indoles / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D007093:Imidazoles; D007211:Indoles; D011500:Protein Synthesis Inhibitors; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; C066304:sertindole