Retention, Metabolism and Elimination of 17α-Ethynyl-Estradiol-3-Methyl Ether (Mestranol)

Abstract

1. Following the intravenous administration of [4-¹⁴C]mestranol (34 μg/kg) to female rats, 44.9 and 3.3% of the dose of radioactivity was excreted in the faeces and urine, respectively, in 3 days. Similarly, after administration of [4-¹⁴C]estradiol (26 μg/kg) 63% was excreted in the faeces and 11% was excreted in the urine in 3 days. Excretion of both compounds declined to 1% dose on the 5th day.

2. A considerable portion (up to 50%) of the radioactivity eliminated in urine and faeces could not be hydrolyzed with β-glucuronidase or by solvolysis. A possible conjugation of metabolites with compounds having SH-groups is discussed.

3. The amount of radioactivity found in brain and adrenals 4 h after injection of [¹⁴C]mestranol was 2-3 times greater than found after injection of [¹⁴C]estradiol. Following administration of [¹⁴C]mestranol extracts of body fat and brain contained mestranol as the main radioactive component.

4. The whole-body radioactivity in mice after administration of [¹⁴C]mestranol was determined. The radioactivity extractable by a mixture of methylene dichloride-ethanol, nearly 40% dose at 2 h after dosage, fell to 1.4% dose at 48 h; the radioactivity not extractable with these solvents, <50% dose at 2 h after dosage, fell to a plateau of 15% dose at 48 h. Most of this non-extractable radioactivity was insoluble in water, and also in ether after acid hydrolysis.

5. After administration of [¹⁴C]mestranol to a female rat, only 2.5% of the radioactivity was expired as ¹⁴CO₂ within 4 days indicating no significant degradation of the steroid nucleus.

6. Some metabolites of mestranol were separated from faecal extracts by column chromatography on alumina. After administration of [3-methyl-³H, 4-¹⁴C]mestranol some metabolites (peaks I, III, VI) have an unaltered 3-methoxy group, while others (II, IV, V) are demethylated to derivatives of ethynylestradiol.