Chemical Properties
Off-White Crystalline Powder
Uses
anti-cancer therapeutic
Uses
Synthetic progestogen exhibiting antimineralocorticoid and antiandrogenic activity.
Description
Drospirenone is a synthetic progestogen that binds to the progesterone, mineralocorticoid, and androgen receptors with binding affinities of 20, 230, and 65% relative to R5020, aldosterone (Item No.
15273), and R1881, respectively.
1 In vivo, drospirenone inhibits spontaneous ovulation in rats (ID
50s = 0.3-1.0 mg/day) when administered orally or subcutaneously.
2 Drospirenone (0.5 mg/animal) administered six times per day maintains pregnancy in ovariectomized pregnant rats. It reduces serum testosterone (Item Nos.
15645 |
ISO60154) and luteinizing hormone in cynomolgus monkeys in a dose-dependent manner. Drospirenone (10 mg/animal per day) also inhibits testosterone-induced growth of the seminal vesicles and prostate in castrated rats. Formulations containing drospirenone have been used as oral contraceptives.
3
Description
The steroid drospirenone in combination with the estrogen agonist ethinylestradiol was
introduced in Germany as a new oral contraceptive for women. This analog of the
aldosterone antagonist spironoiactone can be synthesized in five steps from 3β-hydroxy-
15β,16β-methylene-5-androsten-l7-one. Since its binding profile for steroid receptors is
very similar to progesterone, drospirenone mimics the progestogen agonistic activity as
well as the anti-androgenic and anti-mineralocorticoid properties of the endogenous
hormone. In rats, drospirenone inhibited ovulation at 6.3 mglkglday p.o. Compared with
currently available progestins which lack anti-mineralocorticoid activity, drospirenone did
not cause weight gain that could result from fluid retention in clinical studies. Its
combination with ethinylestradiol was well tolerated and did not engender adverse effects
on blood pressure or plasma lipid levels. Drospirenone is rapidly absorbed in man with an
oral bioavailability of 76%. It is extensively metabolized since over 20 different metabolites
were observed in the urine and in the feces, resulting for instance from hydrolysis of the
lactone in the plasma or reductive conjugation of the enone to the 3-sulfate ester of 45
dihydrodrospirenone. Its elimination is bi-exponential with an initial and a terminal half-life
of 2 and 25-33h respectively.
Originator
Schering AG (Germany)
Definition
ChEBI: Drospirenone is a steroid lactone and a 3-oxo-Delta(4) steroid. It has a role as a contraceptive drug, an aldosterone antagonist and a progestin.
Manufacturing Process
2.75 g of trimethyl sulfoxonium iodide is stirred in 57 ml of dimethyl sulfoxide
with 341 mg of 80% sodium hydride oil suspension for 2 h at room
temperature. The almost clear solution is combined under nitrogen with 2.0 g
of 15α,16α-methylene-3-oxo-4,6-androstadiene-[17(β-1')-spiro-
5']perhydrofuran-2'-one and agitated for 24 h at room temperature. The
mixture is then stirred into ice water, the thus-obtained precipitate is filtered
off, washed with water, and taken up in methylene chloride. After drying and
evaporation, the residue is purified by repeated preparative layer
chromatography, thus obtaining 520 mg of 6β,7β,15α,16α-dimethylene-3-oxo-
4-androstene-[17(β-1')-spiro-5']perhydrofuran-2'-one (drospirenone).
Therapeutic Function
Aldosterone antagonist
General Description
Drospirenone, 3-oxo-6β,7β:15β,16β-dimethylene-17α-pregn-4-en-21,17-carbolactone,differs structurally from all the other commercially availableprogestins. Its structure is similar to that of spironolactone,an MR antagonist, and it does have antimineralocorticoidactivity as well as progestational activity. It isalso reported to have some antiandrogenic effects. Thespirolactone at C17 and the two cyclopropyl groups at C6-C7 and C15-C16 contribute to these unique actions.Drospirenone is the progestin component in the newer oralcontraceptives, Yasmin and Yaz, and in the HRT product,Angeliq.
Biochem/physiol Actions
Drospirenone is a fourth-generation progestin that has antimineralocorticoid, and antiandrogenic activity in addition to potent progestogenic activity. In two recent studies drospirenone appeared to double the risk of venous thromboembolism compared to levonorgestrel, although other studies found little added risk.
