Progesteroneの代謝と不活性化に関する研究

抄録

Recently, many synthetic progestine were reported to be useful for clinical purposes And many of these drugs are effective in both oral and subcutaneous administration, Progesterone, which is natural progestin, however, is inactive when administered orally, The inactivation of orally administered progesterone has been supposed to be due to the ring A reduction of progesterone in the liver. But the metabolism of orally administered progesterone has not yet been well analyzed.
In this experiment, metabolism of peogestserone was studied in three groups of Clauberg rabbits.
1. 3H-Progesterone was administered subcutaneously.
2. 3H-Progesterone was administered orally.
3. 3H-Progesterone subcutaneously and 14C-progesterone orally were administered.
After extraction of free steroid with chloroform (free fraction), the urine was hydorlyzed with β-glucuronidase and extracted with chloroform (glucuronide fraction). The urine was further hydrolyzed with HCl on the boiling water bath and extracted with chloroform (sulfate fraction). These chloroform extracts were washed with NaOH and water, and evaporated. The extracts were combined and the combined extract was adsorbed on alumina with benzene and eluted stepwise with different concentrations of methanol in benzene. Each 10 ml effluent was collected and the radioactivity was counted.
In this experiment the following results were obtained.
1. No marked difference in the distribution of excreted radioactivities in each of free, glucuronide and sulfate fraction bitween Group 1 and 2 was observed.
2. In Group 3, similar 3H/14C ratio was observed in each of free, glucuronide and sulfate fraction.
3. Column chromatography revealed three radioactive peaks. The elution pattern of radioactivities from the column in Group 1 was similar to that in Group 2.
4. In Group 3, no marked difference in the 3H/14C ratio of the three radioactive peaks was observed.
5. One of the urinary metabolite was identified as 20c&-hydroxypregn-4-ene-3-one by paper chromatography, acetylation, deacetylation, chromic acid oxidation and recrystalization.
6. 20α-hydroxypregn-4-ene-3-one was excreted in urine as glucuronide and the radioactivities were counted as 3-4% of the administered doses.
7. In Group 3, urinary excretion of 14C was faster than that of 3H.
8. Experiment with blood, after administration of radioactive progeaterone, revealed that the ratio of radioactivities incorporated into free fraction to the conjugated fraction was 23 times greater in Group 1 than in Group 2.
These results indicate that, in the Clauberg rabbit, the glucuronidation of C-20 reduced matabolite of progesterone, in addition to the ring A reduction, plays a significant role in the inactivation of progesterone in vivo.