DISPOSITION OF THE NOVEL ANTI-SCHIZOPHRENIC DRUG [C-14]OLANZAPINE IN MALE FISCHER-344 AND FEMALE CD RATS FOLLOWING SINGLE ORAL DOSE ADMINISTRATION

These studies comprehensively evaluate the distribution of [C-14]olanz apine iperazinyl)-10H-thieno(2,3-b)-(1,5)benzodiazepine, CAS 132539-06 -1, LY170053) a novel anti-schizophrenic compound, following single or al 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 r ats following a single oral 8 mg/kg dose at 2, 6, 24, 48, 72, and 96 h postdose using quantitative whole-body autoradiographic (QWBA) techni ques in conjunction with image analysis. This study demonstrated that [(14)]olanzapine and/or metabolites were rapidly absorbed and widely d istributed with a t(max) of 2 h postdose in most tissues. Persistent b ut declining concentrations of radiocarbon were detected in feces, kid ney, liver, and Harderian, preputial, and thyroid glands at 96 h postd ose. Placental transfer of [C-14]olanzapine was evaluated at 0.5, 1, 3 , 6, and 24 h postdose on gestation day 12, the mid-point of organogen esis, 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 st udies indicated that all tissues analyzed had a t(max) of 1 or 3 h pos tdose with maternal liver consistently containing high concentrations of radiocarbon. Embryos contained measurable concentrations of radioca rbon throughout the time course of these studies confirming that [C-14 ]olanzapine and/or its metabolites crossed the placenta. Additionally, the disposition of [C-14]olanzapine in milk and plasma of lactating f emale CD rats confirmed pup exposure through milk ingestion.