Development and validation of two chromatographic methods for the quantification of E-6087 and one of its metabolites, E-6132, in rat plasma

The pharmacokinetics of E-6087, a newly developed cyclooxygenase-2 inhibitor, was studied in rats and dogs after single oral and intravenous doses. In both animal species, E-6087 was characterized by a long elimination half-life (20-35 h), a low plasma clearance (0.10-0.22 l h(-1) kg(-1)) and a relatively large volume of distribution (2-6 l kg(-1)). Oral bioavailability was lower in dogs than in rats whereas a faster elimination was found in rats. Multiple peaks were present regardless of administration route and animal species, suggesting the existence of enterohepatic circulation. Gender effect on the pharmacokinetics of E-6087 was only found in rats, with greater exposure and longer elimination in females than in males. Food intake reduced the bioavailability (approximately 22%) with no apparent changes in the absorption rate. After oral dosing of 1, 5 and 25 mg kg(-1) to rats, linearity was lost at the highest dose due to the low aqueous solubility of E-6087. Drug absorption was improved by micronization. E-6087 and E-6132, (a pharmacologically active metabolite), showed different pharmacokinetics. The higher percentage of E-6087 at early times suggests that E-6087 is the main compound responsible for in vivo activity, although E-6132 would contribute to the activity at later times.

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“…E-6016 and E-6113 were used as internal standards of E-6087 and E-6132, respectively [5]. Their chemical structures are shown in Figures 1 and 2.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of E‐6087, a new anti‐inflammatory agent, in rats and dogs

Reinoso

Farrán

Moragon

et al. 2001

Biopharm & Drug Disp

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“…18 The suitability of the method developed was assessed by analyzing human plasma samples from a Phase I clinical trial. In this study, a single oral dose of an aqueous ethanolic solution containing 100 mg of rac-E-6087 was administered to 6 healthy male volunteers between 18 and 45 years of age.…”

Section: Application Of the Methodsmentioning

confidence: 99%

“…Furthermore, the pre-dose samples of the pharmacokinetic study did not show any relevant interference, either. E-6132, a major plasma metabolite, 18 did not interfere with the assay due to the lack of fluorescence at the wavelengths used.…”

Section: Selectivitymentioning

confidence: 99%

Enantioselective HPLC determination of E‐6087, a new COX‐2 inhibitor, in human plasma: Validation and pharmacokinetic application

et al. 2004

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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.

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