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In Vitro Plasma Protein Binding of Zileuton and its N-Dehydroxylated Metabolite

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Summary

An ultrafiltration technique or equilibrium dialysis has been used to study the in vitro human plasma protein binding of racemic zileuton, its individual enantiomers, and its pharmacologically inactive metabolite N-dehydroxyzileuton.

The plasma protein binding of zileuton and N-dehydroxyzileuton over the concentration range of 0.1 to 100 mg/L averaged 93.1 ± 0.22 and 92.0 ± 0.12%, respectively. However, there appeared to be a stereoselective effect, with the R(+) enantiomer of zileuton demonstrating greater binding to plasma proteins than the S(−) enantiomer (96 vs 88%, respectively). Zileuton was bound to both human serum albumin (40 g/L) and α1-acid glycoprotein (1 g/L), although binding affinity to albumin was approximately 3-fold greater. Displacement interactions of zileuton with warfarin, salicylate, theophylline, naproxen, ibuprofen, prednisone, and terfenadine were minimal.

The blood to plasma concentration ratio for zileuton and N-dehydroxyzileuton ranged from 0.65 to 0.68, indicating that these compounds were mainly distributed in the plasma.

Thus, zileuton is approximately 93% bound to plasma proteins at expected therapeutic concentrations in vitro, and this figure is largely unaffected by several commonly prescribed agents with which the drug may be coadministered.

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  1. Biotransformation Department, Abbott Laboratories 46V, AP9, 100, Abbott Park Road, Abbott Park, Illinois, 60064-3500, USA

    Joseph M. Machinist, Michael J. Kukulka & Barbara A. Bopp

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  1. Joseph M. Machinist
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  2. Michael J. Kukulka
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  3. Barbara A. Bopp
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Machinist, J.M., Kukulka, M.J. & Bopp, B.A. In Vitro Plasma Protein Binding of Zileuton and its N-Dehydroxylated Metabolite. Clin-Pharmacokinet 29 (Suppl 2), 34–41 (1995). https://doi.org/10.2165/00003088-199500292-00006

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