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Protein binding of warfarin enantiomers in serum of humans and rats

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Abstract

The protein binding of racemic 14 C-warfarin and 3 H-S(-)-warfarin was determined in individual undiluted serum samples from 31 human subjects and 11 rats. The free fraction value of the R(+) enantiomer was determined indirectly from the free fraction values of the S(−) enantiomer and racemic warfarin, a method which was verified by direct determination of the free fraction of R(+)-warfarin with the unlabeled compound at higher concentrations. The ratio (mean± sd)of free fraction values, R(+):S(−), was 1.32±0.256in man and 1.56±0.351 in the rat;the difference between species is statistically significant (p<0.025).This ratio was independent of the free fraction value of either enantiomer even though there were pronounced intersubject differences in serum protein binding of the anticoagulant. S(−)-Warfarin is eliminated more rapidly than the R(+) enantiomer in man, while the opposite occurs in rats. The results of this study rule out a species difference in serum protein binding as a factor contributing to the difference in elimination kinetics but help to explain the strong correlation in the elimination kinetics of the two enantiomers in individual rats.

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Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14214, Buffalo, New York

    Avraham Yacobi & Gerhard Levy

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  1. Avraham Yacobi
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  2. Gerhard Levy
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Additional information

Supported by Grant GM 20852 from the National Institute of General Medical Sciences of the National Institutes of Health.

This is paper XXVI in the series “Comparative Pharmacokinetics of Coumarin Anticoagulants.” Previous paper: J. T. Slattery, A. Yacobi, and G. Levy,J. Pharm. Sci. (in press).

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Yacobi, A., Levy, G. Protein binding of warfarin enantiomers in serum of humans and rats. Journal of Pharmacokinetics and Biopharmaceutics 5, 123–131 (1977). https://doi.org/10.1007/BF01066216

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  • DOI: https://doi.org/10.1007/BF01066216

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