Stereoselective disposition of the geometric isomers of a novel lipoxygenase cyclo-oxygenase inhibitor in dog and photochemical interconversion of its isomers |
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Authors: | B K Matuszewski S M Kanovsky M L Constanzer K C Yeh W F Bayne |
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Affiliation: | Merck Sharp & Dohme Research Laboratories, West Point, PA 19486. |
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Abstract: | A sensitive (10 ng/mL) and specific high-performance liquid chromatographic (HPLC) assay, with electrochemical (EC) detection, for the geometric isomers of 3-hydroxy-N-(2-phenyl-2-(2-thienyl)ethenyl-5-(trifluoromethyl)benzo(b) thiophene-2-carboxamide in dog and human plasma has been developed. Both isomers strongly absorb light, leading to an efficient E in equilibrium Z photoisomerization. After iv administration of a single isomer (Z) to a dog, only the Zisomer was detected in plasma; no in vivo conversion to the E isomer was observed. However, when a mixture of the E and Z isomers (58.6:41.4) was administered in the same manner to the same dog, the E:Z ratio decreased significantly to 47.5:52.5 six hours after drug administration, indicating stereoselective disposition of the isomers. The elimination of the E isomer was found to be faster than that of the Z isomer. |
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