The Pharmacokinetics of Single Oral Doses of Zileuton 200 to 800mg, its Enantiomers, and its Metabolites, in Normal Healthy Volunteers

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Abstract
The pharmacokinetics of single oral doses of zileuton 200 to 800mg, its R(+) and S(−) enantiomers, and its Af-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 dosenormalised area under the concentration-time curve from zero to infinity (AUC0-∞) 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 AUC-∞ 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 dosenormalised 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 clearances 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.