Establishment of Microanalysis of Prostaglandin Metabolites by GC/MS and Its Clinical Application

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  • 超微量分析法を用いたプロスタノイドの臨床薬学的研究
  • チョウビリョウ ブンセキホウ オ モチイタ プロスタノイド ノ リンショウ ヤクガクテキ ケンキュウ

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Abstract

We established microdetermination methods of prostaglandin (PG) metabolites by GC-selected ion monitoring (GC-SIM) and applied them to the clinical investigations. At first the microdetermination of Δ17-6-keto-PGF1α, a hydrolyzed metabolite of PGI2, is described. An authentic Δ17-6-keto-PGF1α was prepared from eicosapentaenoic acid (EPA) incubated with a homogenate from the bovine aortic intima. [18O]Δ17-6-Keto-PGF1α was synthesized to obtain an internal standard for GC-SIM of Δ17-6-keto-PGF1α. A good linear response over the range of 10 pg-5 ng was demonstrated. Chromatographic conditions using a MP-65HT column presented nearly baseline separation of Δ17-6-keto-PGF1α and 6-keto-PGF1α. Furthermore, a monoclonal antibody against cis-3-hexen-1-ol was prepared and used to separate and/or concentrate Δ17-6-keto-PGF1α in the human blood sera. Using the prepared immunoaffinity columns of this antibody, Δ17-6-keto-PGF1α was clearly detected in the human blood sera by GC/MS analysis. We were able to detect Δ17-6-keto-PGF1α of the amount ranging from 6 to 26 pg/ml in the human blood plasma. The present method can be applied to the determination of Δ17-6-keto-PGF1α in the human urine and plasma. Diabetes mellitus induces platelet alterations such as hyperaggregation. Variations in PG production seem to be related to this phenomenon but the changes in PG levels remain unclear. So we microanalyzed the 11-dehydrothromboxane B2 (TXB2) and 2, 3-dinor-6-keto-PGF1α, which were stable metabolites of TXA2 and PGI2, in the urine and investigated the relationship between the thromboxane/prostacyclin (TX/PGI) ratio and diabetes mellitus. The TX/PGI ratio in the urine of diabetics was higher than that of healthy volunteers. In murine, the TX/PGI ratio of STZ-induced mice was also higher than that of non-induced mice. The ratio of db/db mice also increased with the progress of diabetes mellitus. Furthermore, we investigated the relationship between the retinal vein occlusion (RVO), a thrombotic disease in which the retinal vein is blocked by blood aggregations, and the TX/PGI ratio. The TX/PGI level in patients with the RVO, who were not combine diabetes, was significantly higher than that in healthy volunteers. One of the causes of the RVO may be due to the variation of thromboxane production. This GC-SIM method can be used to determine the TX/PGI ratio in the urine.

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 119 (1), 61-80, 1999

    The Pharmaceutical Society of Japan

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