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OtherDRUG METABOLISM AND DISPOSITION

Effect of Albumin on the Estimation, In Vitro, of Phenytoin Vmax and K m Values: Implications for Clinical Correlation

Linda K. Ludden, Thomas M. Ludden, Jerry M. Collins, Helen S. Pentikis and John M. Strong
Journal of Pharmacology and Experimental Therapeutics July 1997, 282 (1) 391-396;
Linda K. Ludden
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Thomas M. Ludden
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Jerry M. Collins
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Helen S. Pentikis
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Abstract

The effect of bovine serum albumin (BSA) on human liver metabolism,in vitro, of 14C-phenytoin (PHT) was studied. Michaelis Menten parameters were determined for the conversion of PHT to p-hydroxy phenytoin in seven different microsomal preparations with the addition of 0, 2, and 4% BSA. The unboundK m(K m u) values were 30.8 ± 18.6, 1.57 ± 0.21 and 1.50 ± 0.17 μM (mean ± S.D.), respectively; however, there was excellent agreement among the Vmax values (29.1, 31.8 and 31.5 pmol/min/mg). With intact tissue slices, BSA (4%) added to incubations of PHT had a minimal effect on the Vmax values in two of the four livers studied and resulted in a mean K m u value of 2.20 ± 0.59 μM, although theK m u in the absence of BSA was 6.64 ± 3.17. In scaling-up to the whole body, Vmaxvalues were 3.9 and 1.0 mg/kg/day for microsomes and slices, respectively, compared to 5.9 mg/kg/day, in vivo. TheK m u values determined in the presence of albumin in both microsomes and slices were similar to those based on in vivo human steady state data (K m u = 2-3 μM), and the intersubject variation, in vitro, was decreased in the presence of BSA. These findings for phenytoin metabolism suggest that the addition of albumin to incubation media for slices or microsome experiments may yield K m estimates that are more representative of in vivo values.

Footnotes

  • Send reprint requests to: Linda K. Ludden, Department of Pharmaceutical Sciences, College of Pharmacy University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6025.

  • ↵1 This work was presented at The American Society of Clinical Pharmacology and Therapeutics Meeting, March 1996, Orlando, FL.

  • ↵2 Current address: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6025.

  • ↵3 Current address: Drug Metabolism/Pharmacokinetics Department, Rhône-Poulenc Rorer, 500 Arcola Road, Collegeville, PA 19426-0107.

  • Abbreviations:
    BSA
    bovine serum albumin
    HPLC
    high performance liquid chromatography
    PHT
    phenytoin
    pHPPH
    p-hydroxy phenytoin
    fu
    fraction unbound
    Kmu
    unboundK m
    • Received September 20, 1996.
    • Accepted March 3, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 1
1 Jul 1997
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OtherDRUG METABOLISM AND DISPOSITION

Effect of Albumin on the Estimation, In Vitro, of Phenytoin Vmax and K m Values: Implications for Clinical Correlation

Linda K. Ludden, Thomas M. Ludden, Jerry M. Collins, Helen S. Pentikis and John M. Strong
Journal of Pharmacology and Experimental Therapeutics July 1, 1997, 282 (1) 391-396;

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OtherDRUG METABOLISM AND DISPOSITION

Effect of Albumin on the Estimation, In Vitro, of Phenytoin Vmax and K m Values: Implications for Clinical Correlation

Linda K. Ludden, Thomas M. Ludden, Jerry M. Collins, Helen S. Pentikis and John M. Strong
Journal of Pharmacology and Experimental Therapeutics July 1, 1997, 282 (1) 391-396;
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