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Research ArticleArticle

Disposition and Metabolic Fate of Atomoxetine Hydrochloride: Pharmacokinetics, Metabolism, and Excretion in the Fischer 344 Rat and Beagle Dog

Edward L. Mattiuz, G. Douglas Ponsler, Robert J. Barbuch, Paul G. Wood, John H. Mullen, Richard L. Shugert, Qimin Li, William J. Wheeler, Fengjiun Kuo, Preston C. Conrad and John-Michael Sauer
Drug Metabolism and Disposition January 2003, 31 (1) 88-97; DOI: https://doi.org/10.1124/dmd.31.1.88
Edward L. Mattiuz
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G. Douglas Ponsler
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Robert J. Barbuch
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Paul G. Wood
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John H. Mullen
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Richard L. Shugert
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Qimin Li
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William J. Wheeler
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Fengjiun Kuo
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Preston C. Conrad
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John-Michael Sauer
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Abstract

These studies were designed to characterize the disposition and metabolism of atomoxetine hydrochloride [(−)-N-methyl-γ-(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 N-demethylation. 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.

Footnotes

  • Abbreviations used are::
    HPLC
    high pressure liquid chromatography
    LC/MS
    liquid chromatography-mass spectrometry
    AUC
    area under the time verssus plasma concentration curve
    LSC
    liquid scintillation counting
    CID
    collision-induced dissociation
    LC/MS/MS
    combined liquid chromatography-tandem mass spectrometry
    CL
    clearance
    Cmax
    maximal plasma concentration
    Tmax
    time to maximal plasma concentration
    Vss
    volume of distribution
    F
    absolute oral bioavailability
    • Received June 13, 2002.
    • Accepted October 7, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (1)
Drug Metabolism and Disposition
Vol. 31, Issue 1
1 Jan 2003
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Research ArticleArticle

Disposition and Metabolic Fate of Atomoxetine Hydrochloride: Pharmacokinetics, Metabolism, and Excretion in the Fischer 344 Rat and Beagle Dog

Edward L. Mattiuz, G. Douglas Ponsler, Robert J. Barbuch, Paul G. Wood, John H. Mullen, Richard L. Shugert, Qimin Li, William J. Wheeler, Fengjiun Kuo, Preston C. Conrad and John-Michael Sauer
Drug Metabolism and Disposition January 1, 2003, 31 (1) 88-97; DOI: https://doi.org/10.1124/dmd.31.1.88

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Research ArticleArticle

Disposition and Metabolic Fate of Atomoxetine Hydrochloride: Pharmacokinetics, Metabolism, and Excretion in the Fischer 344 Rat and Beagle Dog

Edward L. Mattiuz, G. Douglas Ponsler, Robert J. Barbuch, Paul G. Wood, John H. Mullen, Richard L. Shugert, Qimin Li, William J. Wheeler, Fengjiun Kuo, Preston C. Conrad and John-Michael Sauer
Drug Metabolism and Disposition January 1, 2003, 31 (1) 88-97; DOI: https://doi.org/10.1124/dmd.31.1.88
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