1978 Volume 54 Issue 8 Pages 939-948
The mechanism of the enhanced anti-inflammatory activity of synthetic glucocorticoids has not been established. The most potent and useful glucocorticoids, dexamethasone (16α-methyl-9α-fluoro-prednisolone) and betamethasone (16β-methyl-9α-fluoro-prednisolone), have the same anti-inflammatory potency in humans. But in the rat they have a different anti-inflammatory potency. That is, in the rat dexamethasone is considered to have a potency 160 to 190 times that of cortisol, whereas betamethasone is considered to have a potency 10 to 70 times that of cortisol. This difference is thought to depend upon the fact that in the dexamethasone molecule, the 16-methyl radicle is in the ot-position, whereas in the betamethasone molecule it is in the β-position.
This paper describes the plasma concentration, the tissue distribution and the excretion of dexamethasone and betamethasone following intramuscular administration in Sprague-Daulay male rats. In addition, the urinary metabolites of these glucocorticoids in the free fraction are analysed. These experimental data demonstrate the relationship between the structure and the metabolic fate of these two compounds and clarify the mechanism of enhancement in the anti-inflammatory activity of glucocorticoids by structural changes. The radioisotope-labelled glucocorticoids used were cortisol-4-14C, dexamethasone-1, (2) -3H, and betamethasone-1, 2, 4-3H. Each compound was administered to the rats intramuscularly, and the radioactivities recovered by 75% methanol from plasma, various tissues and feces were measured using a Packard Tricarb Liquid Scintillation Spectrometer. Urinary metabolites were extracted with ethyl acetate, chromatographed in a Frantz Y and Bush B5 system and repurified. The analysis of urinary metabolites was performed using the Porter-Silber reaction, UV absorption, 17-ketonization and the sulphuric acid chromogen spectrum.
The results were as follows :
1) Dexamethasone exhibited longer plasma half-life than betamethasone. The maximum plasma concentration of these two compounds was almost equal.
2) The more potent glucocorticoids, such as dexamethasone and betamethasone, were excreted more slowly in the urine and feces than cortisol.
3) The radioactivities of these two labelled glucocorticoids were recovered more in the liver, kidney and adrenal gland than in the muscle, subcutaneous tissue and brain. And the radioactivities of the more potent dexamethasone were greater in all organs tested than those of the less potent betamethasone.
4) Dexamethasone and betamethasone were less metabolized than cortisol. And the major compounds of their extracts were unchanged materials. But among these two fluorocorticoids, dexamethasone was less metabolized than betamethasone. The main metabolic pathway of the two compounds was as follows : dexamethasone-hydroxylation at C-6, betamethasone-hydroxylation at C-6 and reduction at C-20.
5) In the rat, the more potent dexamethasone exhibits a longer plasma half-life, is excreted more slowly and is less metabolized than the less potent betamethasone.
From the above results it seems logical to assume that the higher concentration of glucocorticoids at the target organs, the greater resistance toward inactivation by the liver, and the slower excretion contribute to the enhancement of the anti-inflammatory activity of synthetic glucocorticoids.
