A RADIOIMMUNOASSAY FOR THE UNSTABLE PULMONARY METABOLITES OF PROSTAGLANDIN-E1 AND PROSTAGLANDIN-E2 - AN INDIRECT INDEX OF THEIR INVIVO DISPOSITION AND PHARMACOKINETICS

  • 1 January 1982
    • journal article
    • research article
    • Vol. 220  (2) , 229-235
Abstract
The peripheral plasma content of the pulmonary metabolite, 13,14-dihydro-15-keto-prostaglandin E2, reflects prostaglandin (PG) E2 biosynthesis and disposition in vivo more reliably than the peripheral plasma content of PGE2 itself. The chemical instability of 13,14-dihydro-15-keto-PGE2 and the multiple fates of its degradation products hinder the development of quantitative assays for the metabolite. These problems were eliminated with an indirect approach. At pH 10.5, intact 13,14-dihydro-15-keto-PGE2 and its degradation products convert uniformly into 11-deoxy-13,14-dihydro-15-keto-11.beta.,16.xi.i-cyclo-PGE2. A radioimmunoassay with a sensitivity of 12-pg for this analytically suitable bicyclic derivative was developed. The accuracy, precision and sensitivity of the method permitted its application to certain intractable problems. Plasmal levels of the pulmonary metabolite can be quantitated and used as an index of the pharmacokinetic disposition of PGE2 because its metabolite forms almost instantaneously and completely, in vivo. In dogs there was a dose-dependent increase in plasma 13,14-dihydro-15-keto-PGE2 concentration after bolus i.v. injections of PGE2. Ten minutes after administration of 30, 10 or 3 .mu.g of PGE2/kg, its plasma metabolite concentrations were 34.1 .+-. 8.4, 6.8 .+-. 0.6 and 2.0 .+-. 0.2 ng/ml (mean .+-. SEM, standard error of the mean, n = 4). The metabolite disappeared from the circulation rapidly with half-lives of 9.9 .+-. 0.2, 9.2 .+-. 0.3 and 7.8 .+-. 0.8 min (mean .+-. SEM, n = 4) for the respective doses noted above. Similar studies with PGE1 were possible because of the predictable cross-reaction between the bicyclic derivatives of 13,14-dihydro-15-keto-PGE2 and 13,14-dihydro-15-keto-PGE1. Because the latter compound is not normally present in mammals, measurments of endogenous 13,14-diydro-15-keto-PGE2 are still accurate. Basal concentrations of 48 .+-. 31 pg/ml (mean .+-. SD, n = 15) in human plasma concur with concentrations measured by gas chromatography/mass spectrometry.

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