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Research ArticleArticle

Effect of Albumin on Phenytoin and Tolbutamide Metabolism in Human Liver Microsomes: An Impact More Than Protein Binding

Cuyue Tang, Yuh Lin, A. David Rodrigues and Jiunn H. Lin
Drug Metabolism and Disposition June 2002, 30 (6) 648-654; DOI: https://doi.org/10.1124/dmd.30.6.648
Cuyue Tang
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Yuh Lin
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A. David Rodrigues
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Jiunn H. Lin
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Abstract

The cytochrome P450 (P450)-dependent conversion of phenytoin (PHT) to p-hydroxy phenytoin (pHPPH), and tolbutamide (TLB) to 4-hydroxy tolbutamide (hydroxy-TLB), in human liver microsomes was studied in the presence of increasing concentrations (0–4%) of bovine serum albumin (BSA). Therefore, the free fraction (fu) of PHT and TLB varied. Whereas the fu of PHT (5 μM) decreased, an increase (3-fold), rather than a decrease in the pHPPH formation rate was observed when BSA (<1%) was present. The stimulation was attributed to a significant decrease in apparentKm. The change, however, was diminished as the BSA concentration reached 4% (PHTfu = 0.2), in which the reaction velocity remained the same as that measured in the absence of BSA. Therefore, unchanged Km (16.2 ± 0.7 μM) and Vmax (9.4 ± 0.2 pmol/min/mg of protein) values were determined based on total PHT concentrations, whereas correction for fu led to an unboundKm (Kmu) of ∼3.2 μM. Similarly, the metabolism of TLB (50 μM) was enhanced (∼2-fold) in the presence of 0.25% BSA but remained only 35% of the control activity (no BSA) at 1% BSA. However, the remaining activity was higher (3-fold) than that determined with an equivalent free concentration of TLB (4 μM) calculated according to itsfu (0.08). The difference became less significant when BSA concentration was 4% (fu < 0.02). Collectively, the results suggest a 2-fold effect of BSA on PHT and TLB hydroxylation: first, facilitation of the reactions via a decrease inKm; second, a decrease infu leading to a drop in reaction rate. For a given P450 reaction, therefore, the effect of BSA may depend upon enzyme affinity, catalytic capacity, and the extent of protein binding.

Footnotes

  • Abbreviations used are::
    BSA
    bovine serum albumin
    PHT
    phenytoin
    OH-TLB
    4-hydroxyl tolbutamide
    pHPPH
    p-hydroxy phenytoin
    MPHT
    (±)-5-(4-methylphenyl)-5-phenylhydantion
    CPPM
    chlorpropamide
    HLM
    human liver microsomes
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry
    fu
    mean unbound fraction of substrate
    • Received December 28, 2001.
    • Accepted February 21, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (6)
Drug Metabolism and Disposition
Vol. 30, Issue 6
1 Jun 2002
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Research ArticleArticle

Effect of Albumin on Phenytoin and Tolbutamide Metabolism in Human Liver Microsomes: An Impact More Than Protein Binding

Cuyue Tang, Yuh Lin, A. David Rodrigues and Jiunn H. Lin
Drug Metabolism and Disposition June 1, 2002, 30 (6) 648-654; DOI: https://doi.org/10.1124/dmd.30.6.648

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Research ArticleArticle

Effect of Albumin on Phenytoin and Tolbutamide Metabolism in Human Liver Microsomes: An Impact More Than Protein Binding

Cuyue Tang, Yuh Lin, A. David Rodrigues and Jiunn H. Lin
Drug Metabolism and Disposition June 1, 2002, 30 (6) 648-654; DOI: https://doi.org/10.1124/dmd.30.6.648
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