title: Disposition of the novel anti-schizophrenic drug [14C]olanzapine in male Fischer 344 and female CD rats following single oral dose administration.
abstract: These studies comprehensively evaluate the distribution of [14C]olanzapine (2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno(2,3-b)-1,5)benzodiazepin e, CAS 132539-06-1, LY170053) a novel anti-schizophrenic compound, following single oral dose administration in male Fischer 344 rats, and pregnant and non-pregnant lactating female CD rats. The disposition of radiocarbon was determined and tissue pharmacokinetics evaluated in male Fischer 344 rats following a single oral 8 mg/kg dose at 2, 6, 24, 48, 72, and 96 h postdose using quantitative whole-body autoradiographic (QWBA) techniques in conjunction with image analysis. This study demonstrated that [14C]olanzapine and/or metabolites were rapidly absorbed and widely distributed with a tmax of 2 h postdose in most tissues. Persistent but declining concentrations of radiocarbon were detected in feces, kidney, liver, and Harderian, preputial, and thyroid glands at 96 h postdose. Placental transfer of [14C]olanzapine was evaluated at 0.5, 1, 3, 6, and 24 h postdose on gestation day 12, the mid-point of organogenesis, by tissue dissection and liquid scintillation spectroscopy (LSC) and on gestation day 18, a time which enabled visualization of fetal tissues by whole-body autoradiography (WBA). The placental transfer studies indicated that all tissues analyzed had a tmax of 1 or 3 h postdose with maternal liver consistently containing high concentrations of radiocarbon. Embryos contained measurable concentrations of radiocarbon throughout the time course of these studies confirming that [14C]olanzapine and/or its metabolites crossed the placenta. Additionally, the disposition of [14C]olanzapine in milk and plasma of lactating female CD rats confirmed pup exposure through milk ingestion.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Chay
authors.forename: J L
authors.initials: JL
authors.lastname: Herman
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001345:Autoradiography; D001569:Benzodiazepines; D005260:Female; D007091:Image Processing, Computer-Assisted; D008297:Male; D008431:Maternal-Fetal Exchange; D008892:Milk / Q000378:metabolism; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D010890:Pirenzepine; D000077152:Olanzapine