[3H]6alpha-methylprogesterone (6MP) was synthesized by selective catalytic tritiation of the delta1-olefinic bond of 6alpha-methylpregna-1,4-diene-3,20-dione. The metabolic clearance rate of 6MP (MCR6MP) was determined in 6 women by the single injection technique. The plasma MCR6MP was 4047 +/- 298 L/day (59 +/- 15 L/day/kg) which was higher than the MCR of progesterone and medroxyprogesterone acetate (6alpha-methyl-17alpha-hydroxy-pregna-4-ene-3,20-dione acetate). The high clearance was not due to binding or metabolism of 6MP by red cells. Although 6MP was bound to CBG with a lower affinity than progesterone, this could not entirely explain the high MCR6MP. When considered with the reports of progesterone and medroxyprogesterone acetate clearance, the present studies suggest that the 6alpha-substitution of progesterone leads to an increased rate of steroid metabolism in women.
PIP: In vivo research has shown that the gestagenic potency of MPA (medroxyprogesterone acetate) is greater than that of progesterone in virtually all species tested. It was hypothesized that this was due to a slower rate of metabolism of MPA relative to progesterone. In women, the clearance rate of the 2 substances was found to be similar, suggesting that the functional groups at the 6alpha- and 17alpha-positions might not influence the rate of progestin metabolism in humans as had been suspected. To test this hypothesis, independent effects of the 6alpha-methyl and the 17alpha-acetoxy substitutions on the metabolism of progesterone were examined. For this purpose, 6alpha-methylprogesterone was synthesized for metabolic studies. The clearance rate of this substance, tested by plasma concentrations, was found to be higher than that of either MPA or progesterone. This rate was not attributable to binding or metabolism by red cells. The differences in clearance rates do not seem to be related to steroid-protein interactions in plasma.