ABSTRACT:These studies were designed to characterize the disposition and metabolism of atomoxetine hydrochloride [(؊)-N-methyl-␥-(2-methylphenoxy)benzenepropanamine hydrochloride; formerly know as tomoxetine hydrochloride] in Fischer 344 rats and beagle dogs. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the majority of its metabolites being excreted into the urine, 66% of the total dose in the rat and 48% in the dog. Fecal excretion, 32% of the total dose in the rat and 42% in the dog, appears to be due to biliary elimination and not due to unabsorbed dose. Nearly the entire dose was excreted within 24 h in both species. In the rat, low oral bioavailability was observed (F ‫؍‬ 4%) compared with the high oral bioavailability in dog (F ‫؍‬ 74%). These differences appear to be almost purely mediated by the efficient first-pass hepatic clearance of atomoxetine in rat. The biotransformation of atomoxetine was similar in the rat and dog, undergoing aromatic ring hydroxylation, benzylic oxidation (rat only), and Ndemethylation. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming O-glucuronide and O-sulfate (dog only) metabolites. Although subtle differences were observed in the excretion and biotransformation of atomoxetine in rats and dogs, the primary difference observed between these species was the extent of first-pass metabolism and the degree of systemic exposure to atomoxetine and its metabolites.

No abstract

No abstract

No abstract

A liquid chromatographic/mass spectrometric assay was developed for the determination of LY355703, a potent anti-tumor drug, in mouse and dog plasma. Empore (3M) C18 solid-phase extraction cartridges were used for sample preparation in conjunction with a positive pressure manifold. Chromatographic separation was obtained with a cyano high-performance liquid chromatographic column and detection was conducted using atmospheric pressure chemical ionization tandem mass spectrometry in the selected reaction monitoring mode. A structural analog, compound LY354504, was used as the internal standard. The assay was validated for the determination of LY355703 in mouse (ICR and NuNu) and dog (beagle) plasma. The lower and upper limits of quantitation were 2.1 and 527 ng ml-1, respectively, using a 0.1 ml plasma aliquot. The signal-to-noise ratio of a typical 2.1 ng ml-1 standard was approximately 40:1. The inter-day precision (relative standard deviation) and accuracy (relative error) derived from the analysis of validation samples at five concentrations ranged from 2.7 to 7.6% and from 4.8 to 4.5%, respectively. Throughput is approximately one sample every 3 min. This assay is simple, sensitive, accurate, precise and is being used to support toxicokinetic studies in dog and mouse.