Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity. Pharmacological characterization in animal models.
Drospirenone (ZK 30595; 6 beta, 7 beta, 15 beta, 16 beta-dimethylen-3- oxo-17 alpha-pregn-4-ene-21, 17-carbo-lactone) is a novel progestogen under clinical development. Potential applications include oral contraception, hormone replacement therapy and treatment of hormonal disorders. Drospirenone is characterized by a pharmacodynamic profile very closely related to that of progesterone. The progestogenic activity of drospirenone has been analysed in a variety of animal models. The compound efficiently promotes the maintenance of pregnancy in rats, inhibits ovulation in rats and stimulates endometrial transformation in the rabbit. Furthermore, drospirenone shows potent antigonadotropic, i.e. testosterone-lowering, activity in male cynomolgus monkeys. The progestogenic potency of drospirenone was found to be in the range of that of norethisterone acetate or cyproterone acetate. Like progesterone, drospirenone has been shown to have an antimineralocorticoid effect in rats and humans. It has now been demonstrated that the compound has a long-lasting natriuretic activity in rats on administration of a daily dose of 10 mg s.c. for three weeks. Under identical conditions, spironolactone, a widely-used antimineralocorticoid, becomes ineffective after the initial treatment phase. Drospirenone exhibits antiandrogenic activity in castrated, testosterone-substituted male rats as shown by dose-dependent inhibition of accessory sex organ growth (prostate, seminal vesicles). In this model, the potency of drospirenone was found to be about one-third that of cyproterone acetate. The compound is devoid of androgenic, estrogenic, glucocorticoid and antiglucocorticoid activity. Possible drug interaction between drospirenone and ethinylestradiol (EE) was also investigated. EE did not interfere with either the progestogenic or the antimineralocorticoid activity of drospirenone. In conclusion, drospirenone represents a novel type of synthetic progestogen since it combines potent progestogenic characteristics with antimineralocorticoid and antiandrogenic activity. Thus, the pharmacological profile of drospirenone is more closely related to that of the natural hormone progesterone than is that of any other synthetic progestogen in use today. Therefore, drospirenone is anticipated to give rise to a number of additional health benefits both for users of oral contraceptives and hormone replacement therapy recipients.
Muhn
P
P
Research Laboratories of Schering AG, Berlin, Germany.
Krattenmacher
R
R
Beier
S
S
Elger
W
W
Schillinger
E
E
D000726:Androgen Antagonists / Q000494:pharmacology*; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D004717:Endometrium / Q000187:drug effects; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D008901:Mineralocorticoids / Q000037:antagonists & inhibitors*; D009919:Orchiectomy; D010052:Ovariectomy; D010060:Ovulation / Q000187:drug effects; D011247:Pregnancy; D011255:Pregnancy Maintenance / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D012733:Sex Differentiation / Q000187:drug effects
D000726:Androgen Antagonists; D000736:Androstenes; D000451:Mineralocorticoid Receptor Antagonists; D008901:Mineralocorticoids; D004997:Ethinyl Estradiol; D011374:Progesterone; C035144:drospirenone