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Rapid CommunicationShort Communication

Phenacetin Pharmacokinetics in CYP1A2-Deficient Beagle Dogs

Valerie J. Whiterock, Daniel G. Morgan, Kimberley A. Lentz, Tami L. Orcutt and Michael W. Sinz
Drug Metabolism and Disposition February 2012, 40 (2) 228-231; DOI: https://doi.org/10.1124/dmd.111.041848
Valerie J. Whiterock
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Daniel G. Morgan
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Kimberley A. Lentz
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Tami L. Orcutt
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Michael W. Sinz
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Abstract

Phenacetin is widely used as an in vitro probe to measure CYP1A2 activity across species. To investigate whether phenacetin can be used as an in vivo probe substrate to phenotype CYP1A2 activity in dogs, beagle dogs previously genotyped for a single nucleotide polymorphism that yields an inactive CYP1A2 protein were selected and placed into one of three groups: CC (wild-type), CT (heterozygous), or TT (homozygous mutants). The dogs were dosed with phenacetin orally at 5 and 15 mg/kg and intravenously at 15 mg/kg. Plasma samples were analyzed by liquid chromatography-tandem mass spectrometry, and phenacetin and its primary metabolite, acetaminophen, were monitored. After intravenous dosing, all groups showed similar exposure of phenacetin irrespective of genotype. After oral dosing at 15 mg/kg, the exposure of phenacetin in CC and CT dogs was similar, but phenacetin exposure was 2-fold greater in TT dogs. Exposure of the metabolite, acetaminophen, was similar in all groups; however, the mean acetaminophen/phenacetin ratio in TT dogs was 1.7 times less than that observed in CC dogs. Similar trends between the groups of dogs with respect to phenacetin exposure were also observed after a lower 5 mg/kg p.o. dose of phenacetin; however, a proportionally greater amount of acetaminophen was generated. Although oral exposure of phenacetin was 2-fold higher and acetaminophen exposure was 2-fold lower in CYP1A2-deficient (TT) dogs, these results were considered modest and suggest that phenacetin is not a selective or robust in vivo probe to measure CYP1A2 enzyme activity in the dog.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:http://dx.doi.org/10.1124/dmd.111.041848.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    AUC
    area under the curve
    AC-3933
    5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine
    YM-64227
    4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one
    PEG 400
    polyethylene glycol 400.

  • Received July 19, 2011.
  • Accepted November 10, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (2)
Drug Metabolism and Disposition
Vol. 40, Issue 2
1 Feb 2012
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Rapid CommunicationShort Communication

PHENACETIN PHARMACOKINETICS IN CYP1A2-DEFICIENT DOGS

Valerie J. Whiterock, Daniel G. Morgan, Kimberley A. Lentz, Tami L. Orcutt and Michael W. Sinz
Drug Metabolism and Disposition February 1, 2012, 40 (2) 228-231; DOI: https://doi.org/10.1124/dmd.111.041848

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Rapid CommunicationShort Communication

PHENACETIN PHARMACOKINETICS IN CYP1A2-DEFICIENT DOGS

Valerie J. Whiterock, Daniel G. Morgan, Kimberley A. Lentz, Tami L. Orcutt and Michael W. Sinz
Drug Metabolism and Disposition February 1, 2012, 40 (2) 228-231; DOI: https://doi.org/10.1124/dmd.111.041848
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