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Research ArticleArticle

Propofol Hydroxylation by Dog Liver Microsomes: Assay Development and Dog Breed Differences

Michael H. Court, Bonnie L. Hay-Kraus, Dennis W. Hill, Albert J. Kind and David J. Greenblatt
Drug Metabolism and Disposition November 1999, 27 (11) 1293-1299;
Michael H. Court
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Bonnie L. Hay-Kraus
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Dennis W. Hill
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Albert J. Kind
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David J. Greenblatt
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Abstract

Pharmacokinetic studies indicate that clearance of propofol, an anesthetic agent, is slower in greyhounds compared with other dog breeds. Biotransformation of propofol to 2,6-diisopropyl-1,4-quinol (4-hydroxypropofol) by cytochrome P-450 in the liver is proposed as a critical initial step in the elimination of this drug in dogs. Breed differences in the activity of this enzyme could therefore explain pharmacokinetic differences. An in vitro propofol hydroxylase assay was developed and then used to compare enzyme activities in liver microsomes from male greyhound, beagle, and mixed-breed dogs (five each). HPLC of incubate identified only one NADPH-dependent metabolite, which had a chromatographic retention time and UV absorbance, fluorescence, and mass spectra that were identical with authentic 4-hydroxypropofol standard. HPLC with fluorescence detection provided a highly sensitive quantitation method for 4-hydroxypropofol with a quantitation limit of 8 ng/ml using optimized excitation/emission wavelengths (288 nm/330 nm, respectively). Estimates of apparentKm and Vmax for propofol hydroxylation by microsomes from a male beagle dog were 7.3 μM and 3.8 nmol/mg/min, respectively. At a substrate concentration of 20 μM, propofol hydroxylase activity was significantly lower (p = .032) in greyhound microsomes (1.7 ± 0.4 nmol/mg/min) compared with beagle microsomes (5.1 ± 1.3 nmol/mg/min) but was not statistically different (p= .42) compared with mixed-breed microsomes (3.1 ± 1.2 nmol/mg/min). These results indicate that there are breed differences in propofol hydroxylase activity and that deficient hydroxylation of propofol by one or more hepatic cytochrome P-450 isoforms may contribute to slow pharmacokinetic clearance of propofol by greyhounds.

Footnotes

  • Send reprint requests to: Michael H. Court, Department of Pharmacology and Experimental Therapeutics, Tufts University, 136 Harrison Avenue, Boston, MA 02111. E-mail:mcourt01{at}emerald.tufts.edu

  • Dr. Court is the recipient of a Special Emphasis Research Career Award from the National Institutes of Health (K01-RR-00104). This work was also supported in part by National Institutes of Health Grants MH-34223 and MH-19924 and a Hill’s Resident Research Grant.

  • Abbreviations used are::
    4-hydroxypropofol
    2,6-diisopropyl-1,4-quinol
    quinone
    2,6-diisopropyl-1,4-quinone
    GC-MS
    gas chromatography-mass spectrometry
    SPE
    solid phase extraction
    λmax
    maximum UV absorption wavelength
    CYP
    cytochrome P-450
    DMSO
    dimethyl sulfoxide
    • Received October 7, 1998.
    • Accepted June 15, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (11)
Drug Metabolism and Disposition
Vol. 27, Issue 11
1 Nov 1999
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Research ArticleArticle

Propofol Hydroxylation by Dog Liver Microsomes: Assay Development and Dog Breed Differences

Michael H. Court, Bonnie L. Hay-Kraus, Dennis W. Hill, Albert J. Kind and David J. Greenblatt
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1293-1299;

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Research ArticleArticle

Propofol Hydroxylation by Dog Liver Microsomes: Assay Development and Dog Breed Differences

Michael H. Court, Bonnie L. Hay-Kraus, Dennis W. Hill, Albert J. Kind and David J. Greenblatt
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1293-1299;
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