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Application of a stereospecific high-performance liquid chromatography assay to a pharmacokinetic study of etodolac enantiomers in humans.
Jamali F, Mehvar R, Lemko C, Eradiri O.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
An HPLC assay suitable for pharmacokinetic analysis of enantiomers of etodolac [(+/-)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b] indole-1-acetic acid] was developed. Following addition of internal standard (IS), (+/-)-2-(4-benzoylphenyl)butyric acid, the constituents were extracted from the specimen into a mixture of isooctane:isopropanol (95:5). The organic layer was evaporated and the drug and IS were sequentially derivatized with ethyl chloroformate and iota(-)-alpha-phenylethylamine. The diastereoisomers thus formed were extracted and chromatographed on a normal-phase column, with a mobile phase consisting of hexane:ethyl acetate:isopropanol (85:15:0.2) at a flow rate of 2 mL/min. The etodolac diastereoisomers were separated with a resolution factor of 6.4 and detected at a wavelength of 280 nm. Excellent linear relationships were found between the peak area ratios (etodolac:IS) and the plasma and urine concentrations (0.2-20 mg/L), with intra- and interday variations of less than 10.1%. The assay was applied to a preliminary pharmacokinetic study following seven repeated oral administrations of 200 mg/12 h of racemic etodolac to two healthy subjects. The plasma concentrations of the active S-(+)-enantiomer were considerably less than those of the inactive antipode (AUC S:R, 2.5:30.9 mg.L-1.h-1) due to a greater volume of distribution of the latter (S, 101 and 135 L versus R, 24 and 17 L). Considerable concentrations of conjugated enantiomers were also found in plasma (AUC conjugated: intact: S, 1.1; R, 0.23).
Publication Types:
PMID: 2976091 [PubMed - indexed for MEDLINE]