ラットにおける合成Glucocorticoidの体内動態

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タイトル別名
  • Metabolic Fate of Synthetic Glucocorticoids in the Rat
  • ラット ニ オケル ゴウセイ Glucocorticoid ノ タイナイ ドウ

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The enhanced anti-inflammatory activity of synthetic glucocorticoids has been attributed solely to their slower metabolism. But the comparative study of metabolic fate of synthetic glucocorticoids has not been reported.<BR>This paper described the absorption, the plasma concentration, the tissue distribution, the tissue affinity, and the excretion of several synthetic glucocorticoids following intramuscular administration in Sprague-Dauly male rats. In addition, the urinary metabolites of synthetic glucocorticoid in the free fraction were analysed. These experimental data demonstrated the relationship between the structure and the metabolic fate of glucocorticoids and clarified the mechanism of the enhancement in the anti-inflammatory activity of glucocorticoids by the structural changes. The glucocorticoids studied contained cortisol, prednisolone, 6α-methylprednisolone, paramethasone and dexamethasone. The radio-isotope labelled glucocorticoids used were cortisol-4-14C, prednisolone-1, 2, 4-3H, 6α-methyl-prednisolone-1, 2-3H, paramethasone acetate-1, (2) -3H and dexamethasone-1, (2) -3H.<BR>Each compound was administrated to the rats intramuscularly and the radioactivities recovered by 75% methanol from plasma, various tissues, urine and feces were measured using a Packard Tricarb Liquid Scintillation Spectrometer. Urinary metabolites were extracted with ethyl acetate, chromatographied in Frantz Y system and Bush B5 system and repurified. The analyses of urinary metabolites were performed using the Porter-Silber reaction, UV absorption, 17-ketonization and sulfuric acid chromogen spectrum.<BR>1) The more potent synthetic glucocorticoids exhibit longer plasma half-lives. The maximum plasma concentration of synthetic glucocorticoids tested did not always correlate with the anti-inflammatory activity.<BR>2) The more potent glucocorticoids such as paramethasone and dexamethasone were excreted more slowly in the urine and feces.<BR>3) Generally the radioactivities of all labelled synthetic glucocorticoids were recovered more in the liver, kidney, adrenal gland and lung than in the muscle, subcutaneous tissue, spleen and brain. And the radioactivities of more potent synthetic glucocorticoids were greater in all organs tested than that of less potent ones and the latter was more rapidly cleared from the organs.<BR>4) Main metabolic pathway of each glucocorticoid was as follows : cortisol : reduction of the Δ4-3-ketone structure and reduction at C-20; prednisolone and 6α-methylprednisolone : reduction at C-20; paramethasone : unchanged materials; dexamethasone : unchanged materials and hydroxylation at C-6. Potent synthetic glucocorticoids, paramethasone and dexamethasone were less metabolized and the major compounds of their extracts were unchanged materials. No evidence of reduction in the Δ4-3-ketone structure of any synthetic glucocorticoid was found. The increased activity of the synthetic anti-inflammatory steroid is mainly accompanied by a decreased rate of the metabolism in the liver.<BR>5) The competitive distributions of simultaneously administrated cortisol-14C and more potent synthetic glucocorticoid in the rat were studied. Cortisol-14C was more rapidly cleared from various organs and excreted in the urine. The more potent glucocorticoids have higher affinities to the target organs.<BR>6) Therefore it seems logical to assume that the higher concentration of glucocorticoids in the target organs, the greater resistance toward inactivation by the liver and the higher tissue affinity to the target organs contribute to the enhancement of the anti-inflammatory activity of synthetic glucocorticoids.<BR>7) Administration of the large doses of glucocorticoids resulted in the greater tissue concentration,

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