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Rapid CommunicationShort Communication

Pharmacokinetics and Metabolism of the Reactive Oxygen Scavenger α-Phenyl-N-tert-butylnitrone in the Male Sprague-Dawley Rat

Mary E. Trudeau-Lame, Amit S. Kalgutkar and Michael LaFontaine
Drug Metabolism and Disposition February 2003, 31 (2) 147-152; DOI: https://doi.org/10.1124/dmd.31.2.147
Mary E. Trudeau-Lame
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Amit S. Kalgutkar
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Michael LaFontaine
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Abstract

The pharmacokinetics of the spin-trap α-phenyl-N-tert-butylnitrone (PBN) was investigated in male Sprague-Dawley rats. Plasma concentrations after i.v. administration (10 mg/kg) declined monoexponentially with a terminal half-life of 2.01 ± 0.35 h and total plasma clearance (CLp) and volume of distribution at steady state (Vdss) averaged 12.37 ± 3.82 ml/min/kg and 1.74 ± 0.5 l/kg, respectively. The observed CLp was in close agreement with the blood clearance (CLb) value (11.5 ml/min/kg) predicted from in vitro liver microsomal incubations suggesting that PBN CLp in rats is predominantly due to hepatic metabolism. Peak plasma concentration (Cmax) following p.o. (20 mg/kg) and s.c. (30 mg/kg) PBN administration was 7.35 ± 1.92 and 3.56 ± 0.66 μg/ml, whereas the area under the concentration-time curve from 0 to infinity was 23.89 ± 5.84 and 15.96 ± 3.10 μg-h/ml, respectively. The mean oral bioavailability of PBN was 85.63 ± 20.93%. Biotransformation studies indicated the P450 2C11-catalyzed hydroxylation of PBN to M1. Potential sites of hydroxylation included the benzylic carbon resulting in phenyl-N-tert-butylhydroxamic acid or the phenyl ring that would afford α-hydroxyphenyl-N-tert-butylnitrone (HOPBN). The structure of M1 was established as α-4-Hydroxyphenyl-N-tert-butylnitrone (4-HOPBN) on the basis of: 1) obvious LC Rtdifferences between M1 and the authentic hydroxamate standard, 2) P450 catalyzed hydroxylation of [2H]PBN that contained a deuterium instead of a hydrogen atom on its benzylic position and which afforded [2H]M1, and 3) comparison of the liquid chromatography-tandem mass spectrometry properties with a synthetic 4-HOPBN standard. We speculate that 4-HOPBN is an “active” PBN metabolite that provides an additive effect to the pharmacological action of PBN in vivo.

Footnotes

  • Abbreviations used are::
    PBN
    α-phenyl-N-tert-butylnitrone
    BHT
    butylated hydroxy toluene
    3-NPA
    3-nitropropionic acid
    P450
    cytochrome P450
    4-HOPBN
    α-4-hydroxyphenyl-N-tert-butylnitrone
    LC/MS/MS
    liquid chromatography-tandem mass spectrometry
    CL′int
    intrinsic clearance
    CLb
    blood clearance
    AUC
    area under the plasma concentration-time curve
    CLp
    total plasma clearance
    Vdss
    volume of distribution at steady state
    F
    relative bioavailability
    Cmax
    peak plasma concentration
    Tmax
    time for maximal oral exposure
    Rt
    retention time
    CID
    collision-induced dissociation
    structure A
    phenyl-N-tert-butylhydroxamic acid
    structure B (HOPBN)
    hydroxyphenyl-N-tert-butylnitrone
    • Received July 31, 2002.
    • Accepted November 12, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (2)
Drug Metabolism and Disposition
Vol. 31, Issue 2
1 Feb 2003
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Rapid CommunicationShort Communication

Pharmacokinetics and Metabolism of the Reactive Oxygen Scavenger α-Phenyl-N-tert-butylnitrone in the Male Sprague-Dawley Rat

Mary E. Trudeau-Lame, Amit S. Kalgutkar and Michael LaFontaine
Drug Metabolism and Disposition February 1, 2003, 31 (2) 147-152; DOI: https://doi.org/10.1124/dmd.31.2.147

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Rapid CommunicationShort Communication

Pharmacokinetics and Metabolism of the Reactive Oxygen Scavenger α-Phenyl-N-tert-butylnitrone in the Male Sprague-Dawley Rat

Mary E. Trudeau-Lame, Amit S. Kalgutkar and Michael LaFontaine
Drug Metabolism and Disposition February 1, 2003, 31 (2) 147-152; DOI: https://doi.org/10.1124/dmd.31.2.147
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