abbott-66193 and zileuton

The diurnal variation in the pharmacokinetic parameters of zileuton were evaluated in 12 healthy male volunteers in a three-period study. Periods I and II constituted a balanced, randomized, crossover study in which a participant received a single dose of 600-mg zileuton either at 7 AM or 11 PM. In period III all participants received 600-mg doses four times daily for 5 days. The differences between the pharmacokinetics of single doses of zileuton administered at 7 AM and 11 PM were not statistically significant. Plasma concentration-time profiles of zileuton during the four daily dose intervals at steady state were also similar. Values for the pharmacokinetic parameters of zileuton after multiple doses were similar to those after single doses, with a minimal accumulation of the drug after multiple doses. Overall, there was little or no diurnal variation in the pharmacokinetic parameters of zileuton after single and multiple doses.

Topics: Adolescent; Adult; Circadian Rhythm; Cross-Over Studies; Humans; Hydroxyurea; Lipoxygenase Inhibitors; Male; Urea

The pharmacokinetics and pharmacodynamics of zileuton were determined after oral administration of single dose (600mg) and multiple dose regimens [600mg every 8 hours (q8h regimen) and 600mg every 6 hours (q6h regimen)] in 12 healthy male subjects aged 18 to 50 years. Steady-state park plasma concentration (Cmax), time to Cmax, apparent total plasma clearance, and apparent terminal phase volume of distribution values after the q8h and q6h regimens were 3.07 +/- 1.13 and 4.37 +/- 1.02 mg/L, 1.5 +/- 0.9 and 1.5 +/- 0.9 hours, 793 +/- 233 and 579 +/- 162 ml/min (47.6 and 34.7 L/h), and 179 +/- 126 and 115 +/- 29L, respectively (mean +/- SD). Trough zileuton plasma concentrations (Cmin) immediately before the morning dose were higher than Cmin immediately before the afternoon dose, suggesting a diurnal variation in the pharmacokinetics of zileuton. Accumulation of zileuton occurred with more frequent dose administration, although there was no unexpected accumulation of the parent drug or the N-dehydroxyzileuton metabolite. The q6h regimen of zileuton 600mg was superior to the q8h regimen in maintaining trough plasma concentrations of zileuton above 1.5 mg/L, corresponding to approximately 70 to 80% inhibition of leukotriene B4 biosynthesis.

Topics: Adolescent; Adult; Chromatography, High Pressure Liquid; Circadian Rhythm; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Fasting; Humans; Hydroxylation; Hydroxyurea; Leukotriene B4; Lipoxygenase Inhibitors; Male; Middle Aged; Stereoisomerism; Urea; White People

The pharmacokinetics of single oral doses of zileuton 200 to 800mg, its R(+) and S(-) enantiomers, and its N-dehydroxylated and glucuronide metabolites have been investigated in a randomised study in 16 normal male healthy volunteers. Zileuton was 93.4% bound to plasma proteins. The overall dispositional pharmacokinetics of zileuton racemate appeared to be linear. The mean dose-normalised area under the concentration-time curve from zero to infinity (AUC0-infinity) remained constant, while the mean dose-normalised peak plasma concentration (Cmax) decreased with the increase in dose, possibly because of dissolution rate-limited absorption at the higher doses. The R(+) and S(-) enantiomers of zileuton may have similar absorption profiles, although the apparent total plasma clearance of the S(-) enantiomer was 49 to 76% higher than the corresponding values for the R(+) enantiomer. The AUC0-infinity of each enantiomer increased proportionately with dose. The pharmacokinetics of the N-dehydroxylated metabolite of zileuton were highly variable, with a more than dose-proportional increase in the mean dose-normalised Cmax and area under the concentration-time curve from zero to 24 hours. The elimination of the glucuronide metabolites of the R(+) and S(-) enantiomers of zileuton was formation rate-limited. The mean percentage of the administered zileuton dose recovered in urine as glucuronide metabolites ranged from 73.1 to 76.5% and showed no dose-related differences. The renal clearance of the glucuronide metabolites of zileuton exceeded the normal glomerular filtration rate, suggesting that these metabolites may be excreted through renal tubular secretion in addition to filtration.

Topics: Absorption; Administration, Oral; Adult; Analysis of Variance; Biological Availability; Blood Proteins; Chromatography, High Pressure Liquid; Cross-Over Studies; Dose-Response Relationship, Drug; Glomerular Filtration Rate; Glucuronates; Half-Life; Humans; Hydroxylation; Hydroxyurea; Kidney Tubules, Proximal; Lipoxygenase Inhibitors; Male; Middle Aged; Protein Binding; Stereoisomerism; Urea

A rapid and sensitive assay was developed for the measurement of plasma concentrations of zileuton racemate, a potent inhibitor of 5-lipoxygenase. Zileuton and its inactive N-dehydroxylated metabolite were extracted from human, monkey, and rat plasma by use of a solid-phase extraction column (Analytichem Bond Elut). The compounds were then separated by reverse-phase high performance liquid chromatography (HPLC) on a Supelcosil LC-18 column and quantified on the basis of ultraviolet absorption at 260nm relative to an internal standard. The extraction recovery of zileuton, as determined by HPLC assay, was 77.9 +/- 1.7%. Recovery of the metabolite was 85.8 +/- 0.7%. Calibration curves for both compounds were linear over the zileuton concentration range 0.01 to 10.0 mg/L (correlation coefficients > 0.987), while the intra- and interassay coefficients of variation were < 15.6%. In practice, > 97% of blinded daily spiked control samples for zileuton and > 90% of those for the metabolite were within 10% of their target concentrations.

Topics: Animals; Calibration; Chromatography, High Pressure Liquid; Drug Stability; Haplorhini; Humans; Hydroxylation; Hydroxyurea; Lipoxygenase Inhibitors; Rats; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Spectrophotometry, Ultraviolet; Stereoisomerism; Urea

In vitro studies were conducted to identify the hepatic cytochrome P450 (CYP) forms involved in the oxidative metabolism of [14C]zileuton (ABT-077) and its N-dehydroxylated metabolite, [14C]Abbott-66193, by human liver microsomes. The two compounds were metabolized by parallel pathways to form the corresponding ring-hydroxylated and diastereomer sulfoxide metabolites. Results suggested that whereas the metabolism of zileuton and Abbott-66193 were mediated by the same CYP forms, the CYP forms responsible for hydroxylation (CYP1A2 and CYP2C9/10) were distinct from those involved in sulfoxidation (CYP3A > CYP2C9/10). Sulfoxidation (zileuton, Km = 0.82 +/- 0.40 mM, Vmax = 39.1 +/- 21.8 pmol/min/mg; Abbott-66193, Km = 0.23 +/- 0.06 mM, Vmax = 507 +/- 215 pmol/min/mg; mean +/- SD, N=3) was highly correlated with the CYP3A-specific erythromycin N-demethylase activity (r=0794-0.856; p<0.01, N=11) in human microsomes and was inhibited (32-67%) by ketoconazole and troleandomycin. In addition, purified recombinant human CYP3A4/rat NADPH-P450 reductase fusion protein catalyzed only the sulfoxidation of zileuton and Abbott-66193; no hydroxylated metabolites were detected. On the other hand, hydroxylation of the two compounds (zileuton, Km = 0.34 +/- 0.25 mM, Vmax = 17.8 +/- 5.58 pmol/min/mg; Abbott-66193,Km = 0.39 +/- 0.14 mM, Vmax = 1061 +/- 220 pmol/min/mg) was significantly correlated with 7-ethoxyresorufin O-deethylase (CYP1A2; r=0.652-0.762; p<0.01, N=11) and tolbutamide methyl hydroxylase (CYP2C9/10; r=0.863-0.935; p<0.01, N=10) activity in human liver microsome, and was inhibited (26-51%) by well-known CYP1A2 inhibitors (furafylline and alpha-naphthoflavone). Furthermore, microsomes from human B-lymphoblastoid cells expressing CYP1A2 catalyzed only the hydroxylation of zileuton and Abbott-66193; sulfoxide were not formed. Abbott-66193 was a better substrate for CYP2C9/10, when compared with zileuton: 1) the effect of sulfaphenazole on hydroxylation in human liver microsomes was more pronounced for Abbott-66193 than zileuton (56% vs. 9% inhibition); and 2) the rate of Abbott-66193 hydroxylation by purified CYP2C9 was almost 30-fold greater than that of zilueton.

Topics: Cytochrome P-450 Enzyme System; Humans; Hydroxylation; Hydroxyurea; In Vitro Techniques; Isoenzymes; Lipoxygenase Inhibitors; Microsomes, Liver; Propranolol; Theophylline; Urea