warfarin and zileuton

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Bronchodilator Agents; Double-Blind Method; Drug Interactions; Humans; Hydroxyurea; Lipoxygenase Inhibitors; Theophylline; Warfarin

A double-blind parallel randomised study was conducted to assess the effects of multiple oral doses of zileuton (600mg every 6 hours) or matching placebo on the steady-state pharmacokinetics and pharmacodynamics of warfarin titrated to a prothrombin time of 14 to 18 seconds in 24 healthy adult male volunteers. Serial blood samples were collected for assessment of prothrombin times and R- and S-warfarin plasma concentrations. Coadministration of zileuton and warfarin had no effect on S-warfarin pharmacokinetics but statistically significantly increased mean R-warfarin plasma concentrations and decreased mean R-warfarin total oral plasma clearance compared with warfarin alone (by 15%). This stereoselective interaction was accompanied by an increase in mean morning (predose) and evening (12-hour postdose) prothrombin times from 17.5 to 19.8 seconds and 17.1 to 19.1 seconds, respectively; the corresponding changes in the placebo group were from 18.1 to 18.8 seconds and 17.3 to 17.5 seconds. Thus, multiple dose administration of zileuton appears to significantly alter steady-state R-warfarin pharmacokinetics and pharmacodynamics. Careful monitoring of prothrombin times with appropriate dose titration of warfarin is recommended with concurrent therapy of zileuton and warfarin.

Topics: Administration, Oral; Adult; Analysis of Variance; Anticoagulants; Blood Coagulation; Blood Specimen Collection; Chromatography, High Pressure Liquid; Double-Blind Method; Drug Interactions; Humans; Hydroxyurea; Lipoxygenase Inhibitors; Male; Prothrombin Time; Reproducibility of Results; Stereoisomerism; Warfarin

2-acetylbenzothiophene-S-oxide (2-ABT-S-oxide or M1) is a reactive metabolite of zileuton, a drug used in the treatment of asthma and is capable of conjugating with glutathione in vitro. Human serum albumin (HSA) is the most abundant protein in plasma and plays a critical role in detoxifying reactive oxygen species. The current research is focused on understanding the interaction between M1 and HSA. The stability studies revealed the half-life of M1 to be about 0.85 h in HSA, 1.82 h in human plasma, and 4.48 h in phosphate-buffered saline (PBS) as determined by first-order approximation. The alkylation rate constant k for HSA was 20 M(-1) min(-1). After quenching with acetonitrile, the half-life of M1 did not change significantly, indicating that M1 is covalently bound to HSA. LC-MS and LC-MS/MS analysis of human plasma revealed the M1 alkylated peptide P (m/z 870) formed by HSA conjugation and concomitant water elimination. The specific amino acid on HSA bound to M1 was identified as Cys-34. This alkylation is observed to be concentration- and incubation-time-dependent in human plasma. HSA oxidized by N, N'-diacetyl-L-cystine exhibits a compromised ability of HSA to react with M1. The alkylated HSA diminished the binding affinity for warfarin. Furthermore, the alkylation was found to be irreversible in the dialysis experiment. In addition, M1 decomposes to 2-ABT in the presence of HSA, presumably acting as an oxidant. The formation of 2-ABT in the incubation and the self-condensation of M1 in PBS indicate that the alkylation of Cys-34 is only one of a number of reactions that occur in the presence of HSA. Irreversible protein modification may potentially lead to a loss of its function. HSA irreversible alkylation represents a model for other proteins to be potentially toxic and thus may help explain zileuton hepatotoxicity.

Topics: Alkylation; Anti-Asthmatic Agents; Binding, Competitive; Chemical and Drug Induced Liver Injury; Chromatography, Liquid; Half-Life; Humans; Hydroxyurea; Ibuprofen; Models, Biological; Serum Albumin; Tandem Mass Spectrometry; Thiophenes; Warfarin

Topics: Adolescent; Adult; Asthma; Child; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Drug Interactions; Humans; Hydroxyurea; Intestinal Absorption; Leukotrienes; Lipoxygenase Inhibitors; Propranolol; Theophylline; Warfarin

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.

Topics: Adult; Anti-Allergic Agents; Anti-Inflammatory Agents; Anticoagulants; Blood Proteins; Chromatography, High Pressure Liquid; Drug Interactions; Female; Hematocrit; Humans; Hydroxylation; Hydroxyurea; Ibuprofen; In Vitro Techniques; Isotope Labeling; Lipoxygenase Inhibitors; Male; Naproxen; Prednisolone; Protein Binding; Salicylates; Stereoisomerism; Terfenadine; Theophylline; Warfarin