E-6087 is a nonsteroidal anti-inflammatory compound that selectively inhibits cyclooxygenase-2. Because E-6087 has a chiral center, this compound is a racemic mixture of two stereoisomers, (+)-(R)-E-6087 (E-6231) and (-)-(S)-E-6087 (E-6232). A normal-phase liquid-chromatographic method for the enantioselective determination of E-6087 in human plasma was developed and validated. The samples were extracted using solid-phase extraction cartridges containing C(18) sorbent, and the extracts were redissolved in absolute ethanol and injected into the chromatographic system. The enantiomeric separation was achieved on a chiral stationary-phase column of derivatized amylose, and the enantiomers were quantified by fluorescence detection. The method was validated for drug concentrations ranging from 5 to 400 ng/ml for both enantiomers. No peaks interfering with the quantification of enantiomers were observed. The limit of quantification was 5 ng/ml, with precision expressed as a coefficient of variation lower than 10.6% and accuracy expressed as relative error lower than 12.2%. The utility of this method was demonstrated by analysis of plasma samples from healthy volunteers given an oral dose of rac-E-6087. Peak plasma levels of E-6231 were higher than levels obtained for E-6232. Results were consistent with those obtained with a conventional reversed-phase method used for determination of the racemic compound.
1. The pharmacokinetics of cizolirtine citrate, a new analgesic compound, were studied in the rat and dog following single oral and intravenous doses. 2. Absorption of radioactivity was fast and complete regardless of the species, and no dose and food-related differences were found. However, the elimination half-life of unchanged cizolirtine was shorter in rat than in dog. 3. Tissue distribution of total radioactivity in rat differed widely and a high affinity for liver, kidney, gastrointestinal and pigmented tissues was observed. In blood and almost all tissues the highest concentrations were reached at 20 min; beyond that time the decline of radioactivity in most tissues was parallel to that in blood. 4. The percentage of radioactivity excreted in the rat was 68% in urine and 21% in faeces, the latter being apparently due to drug enterohepatic circulation. In the dog, 92 and 4% of the radioactivity was found in urine and faeces respectively. The contribution of renal excretion to cizolirtine elimination was <5% in rat and 20% in dog. Twelve metabolites were detected in rat and six in the dog by radio-hplc analysis of urine.
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