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.

Abstract

Abstract. The non-protein bound percentage of ST-1435 was measured by centrifugal ultrafiltration-dialysis in undiluted female serum at 37°C. It was found that as much as 13% of ST-1435 in serum is not bound to proteins. The results also show that the affinities of SHBG and CBG of ST-1435 are very low and that SHBG and CBG do not bind ST-1435 under physiological conditions in serum. We suggest that ST-1435 is bound mainly to serum albumin, and that the binding to that accounts for more than 87% of total serum ST-1435 concentrations. During the treatment period of 3 months, 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 metabolised 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 endogeneous sex steroid hormones or their distribution in plasma. Therefore, side effects such as acne or hirsutism are unlikely to develop as a result of sustained administration of this potent progestin.