| Autor: |
Park, Young Han, McCue, Bette A., Dobbs, Richard E., York, Billie M., Brazzell, R. Kim |
| Zdroj: |
Journal of Pharmaceutical Sciences; July 1988, Vol. 77 Issue: 7 p591-595, 5p |
| Abstrakt: |
Two selective high-performance liquid chromatographic (HPLC) methods have been developed for the quantitative determination of spiro-(2-fluoro-9H-fluorene-9,4′-imidazolidine)-2′,5′-dione (AL01567; 1) in plasma and urine, with an assay sensitivity of 0.25 μg/mL for plasma and 0.13 μg/mL for urine. The plasma assay procedure involved precipitation of proteins with acetonitrile followed by dilution with water. The diluted supernatant was analyzed on an ODS column eluting with acetonitrile:0.5% phosphoric acid (30:70) adjusted to pH 7.2 with concentrated ammonium hydroxide. The urine assay procedure involved extraction of 1with 10% n-butanol in hexane, followed by back extraction with 0.05 M sodium hydroxide. The basic extract was neutralized and analyzed on a phenyl column eluting with acetonitrile:10 mM potassium phosphate (30:70; monobasic, pH 5.6). The pharmacokinetics of 1 was investigated in humans following single and multiple oral doses. The elimination half-life from 12 normal subjects following single 100–400-mg oral doses was independent of dose, and the overall mean half-life was 66 ± 9 h. The overall mean oral clearance (assuming a bioavailability of 100%) was 11 ± 3 mL/min, and the mean apparent volume of distribution was 59 ± 13 L. The mean urinary recovery of intact drug during the first 24 h after dosing was 1.2 ± 0.4% of the administered dose. During once daily 100-mg oral dosing of 1 to five subjects for 21 d, plasma concentrations of 1 reached apparent steady-state by 7 d. The mean apparent terminal elimination half-life after the last dose on Day 21 was 49 ± 4 h, which is shorter than the mean 72 ± 6-h half-life observed in a single 100-mg dose study. The reduced half-life after multiple doses suggests the possibility of time-dependent pharmacokinetics of 1which may result from enzyme induction during multiple dosing. |
| Databáze: |
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