Serum non-protein bound percentage and distribution of the progestin ST-1435: no effect of ST-1435 treatment on plasma SHBG and CBG binding capacities

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Abstract
The non-protein bound percentage of ST-1435 was measured by centrifugal ultrafiltration-dialysis in undiluted female [human] serum at 37.degree. C. As much as 13% of ST-1435 in serum is not bound to proteins. The affinities of SHBG [sex hormone binding globulin] and CBG [corticosteroid binding globulin] of ST-1435 are very low and that SHBG and CBG do not bind ST-1435 under physiological conditions in serum. Apparently ST-1435 is bound mainly to serum albumin, and the binding to that accounts for more than 87% of total serum ST-1435 concentrations. During the treatment period of 3 mo., no change in SHBG or CBG binding levels was observed when ST-1435 was administered parenterally. The lack of any interaction between ST-1435 and high affinity serum steroid binding proteins, and the very high percentage of non-protein bound ST-1435 in serum, probably explain its extremely high biological potency at the hypothalamic-pituitary level, when compared for example with d-norgestrel. For the same reason, practically all the ST-1435 in hepatic portal blood is probably taken-up and very rapidly metabolized by the liver. This may explain why oral administration of ST-1435 results in low and inadequate plasma concentrations for contraceptive purposes, while alternative parenteral routes of administration result in relatively much higher serum concentrations of the steroid. Finally, because ST-1435 does not bind to SHBG and CBG under physiological conditions, and does not change plasma SHBG and CBG binding capacities, ST-1435 treatment will not indirectly alter the amounts of endogenous sex steroid hormones or their distribution in plasma. Side effects such as acne or hirsutism are unlikely to develop as a result of sustained administration of this potent progestin.