The progestin ST 1435--rapid metabolism in man

Area of Science:

• Pharmacology and Toxicology
• Reproductive Endocrinology

Background:

• ST 1435 (Nestorone) demonstrates high contraceptive potency via parenteral administration.
• Oral administration of ST 1435 is ineffective in animals due to extensive first-pass metabolism.
• ST 1435 has been considered for lactational contraception, relying on infant metabolism.

Purpose of the Study:

• To investigate the metabolism of ST 1435 in humans following oral, intravenous, and transdermal administration.
• To compare the bioavailability and metabolic profiles across different routes of ST 1435 delivery.

Main Methods:

• Developed HPLC fractionation and ST 1435-RIA detection methods using rat models.
• Administered ST 1435 orally (10 mg), intravenously (0.1 mg), and transdermally (4.5-9.0 mg) to female volunteers.
• Analyzed serum samples using ST 1435-RIA and competitive receptor binding assays with human uterine progesterone receptors (hPR).

Main Results:

• Oral ST 1435 in humans showed rapid metabolism, with a short half-life (t1/2 ≈ 1-2h) and minimal detectable parent compound after 24h.
• A small fraction of biologically active ST 1435 appears to escape first-pass metabolism after oral intake in humans.
• Intravenous and transdermal administration resulted in detectable ST 1435, suggesting better bioavailability compared to oral route.
• Bioavailability of oral ST 1435 is low, comparable to a much lower intravenous dose.

Conclusions:

• Oral ST 1435 undergoes rapid metabolism in humans, similar to observations in rats.
• Sustained parenteral administration can overcome the rapid metabolism associated with oral intake.
• Further evaluation of ST 1435 for lactational contraception is warranted, despite rapid oral metabolism.