A Gas Chromatographic-Mass Spectrometric Method for the Evaluation of Bioconversion of Indomethacin Prodrugs into the Parent Drug

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The administration of a deuterium-labeled drug together with a prodrug made it possible to determine the bioconversion rate of the prodrug into the parent compound accurately in dogs. Deuterated indomethacins were prepared from acetaldehyde p-methoxyphenylhydrazone in four steps. Indomethacin in blood plasma was derivatized into the hexafluoroisopropyl ester and determined by means of selected ion monitoring employing indomethacin-d_9 as an internal standard. When a single dose of indomethacin or oxametacin was orally given to dogs, the time courses of plasma level of indomethacin were remarkably different from one another. This result implied that the bioconversion rate of oxametacin into indomethacin could not be directly estimated from the area under the drug concentration-time curve (AUC) value. When a mixture of indomethacin-d_4 and oxametacin was administered to three dogs, the ratios of the AUC value of the nonlabeled indomethacin derived from oxametacin to that of the labeled indomethacin in the dogs were found to be almost equal. This approach was also applicable to the estimation of acemetacin. It has been demonstrated that the bioavailabilities of oxametacin and acemetacin can be fairly accurately evaluated with a small number of animals by the combined use of labeled indomethacin and selected ion monitoring.
公益社団法人日本薬学会の論文
1983-06-25