title: In vitro plasma protein binding of zileuton and its N-dehydroxylated metabolite.
abstract: 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 alpha 1-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.
authors.affiliation: Biotransformation Department, Abbott Laboratories, Abbott Park, Illinois, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Machinist
authors.forename: M J
authors.initials: MJ
authors.lastname: Kukulka
authors.forename: B A
authors.initials: BA
authors.lastname: Bopp
mesh_terms: D000328:Adult; D018926:Anti-Allergic Agents / Q000097:blood / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000494:pharmacology; D000925:Anticoagulants / Q000097:blood / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D005260:Female; D006400:Hematocrit; D006801:Humans; D006900:Hydroxylation; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D007052:Ibuprofen / Q000097:blood / Q000494:pharmacology; D066298:In Vitro Techniques; D007553:Isotope Labeling; D016859:Lipoxygenase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics; D008297:Male; D009288:Naproxen / Q000097:blood / Q000494:pharmacology; D011239:Prednisolone / Q000097:blood / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D012459:Salicylates / Q000097:blood / Q000494:pharmacology; D013237:Stereoisomerism; D016593:Terfenadine / Q000097:blood / Q000494:pharmacology; D013806:Theophylline / Q000097:blood / Q000494:pharmacology; D014859:Warfarin / Q000097:blood
chemical_list: D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D001798:Blood Proteins; D016859:Lipoxygenase Inhibitors; D012459:Salicylates; D009288:Naproxen; D014859:Warfarin; D016593:Terfenadine; D011239:Prednisolone; D013806:Theophylline; C063449:zileuton; D007052:Ibuprofen; D006918:Hydroxyurea