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Pharmacotherapeutic group (ATC): Progestogens and estrogens, fixed combinations. ATC Code: G03AA12.
Pharmacology: Pharmacodynamics: LIPZ and LIPZ ED is a combination oral contraceptive consisting of an estrogen called ethinylestradiol and a progestin called drospirenone. Estrogen-progestin combinations produce a contraceptive effect by suppressing the hypothalamic-pituitary system, which results in prevention of ovulation. Specifically, the estrogen acts mainly by suppressing secretion of follicle-stimulating hormone (FSH), resulting in prevention of follicular development and the rise of plasma estradiol concentration. In turn, the progestin appears to act mainly by inhibiting the preovulatory rise of luteinizing hormone (LH). Therefore, long-term administration of these combination products results in inhibition of both FSH and LH secretion. The effects on gonadotropins, combining with the alteration in the genital tract, including cervical mucus (which inhibits sperm penetration) and the endometrium (which reduces the likelihood of implantation), may contribute to contraceptive effectiveness.
Pharmacokinetics: Absorption: Contraceptive steroids are generally well absorbed from the GI tract. Following oral administration, the absolute bioavailability is 76% for drospirenone and 40% for ethinylestradiol, with peak plasma concentration of both drugs being reached in about 1-2 hours after a dose. The mean peak concentration following single-dose oral administration of drospirenone 3 mg (in combination with ethinylestradiol 30 mcg) was reported to be 36.9 ng/mL at about 1.7 hours.
Distribution: Drospirenone is about 97% protein bound, presumably to albumin. Ethinylestradiol is about 98% protein bound, mainly to albumin. Both drugs do not appear to bind to Sex hormone binding globulin (SHBG). Contraceptive steroids may be distributed into bile, and, in small amounts, into milk.
Metabolism: Drospirenone is metabolized only to a minor extent in vitro, mainly by CYP3A4, to inactive metabolites. Ethinylestradiol appears to undergo extensive first-pass metabolism. It is mainly metabolized via aromatic hydroxylation by CYP3A4. The major hydroxylated metabolite of ethinylestradiol is 2-hydroxy-ethinylestradiol, which is thought to contribute to some of the adverse cardiovascular effects of the drug. The hydroxylated metabolite is further metabolized by methylation and glucuronidation. Ethinylestradiol and its metabolites undergo glucuronide and sulfate conjugation, which consequently undergoes extensive enterohepatic circulation.
Excretion: Contraceptive steroids are excreted in urine and feces, principally as glucuronide and sulfate conjugates of the drugs and metabolites. The elimination half-life has been reported to be 30 hours for drospirenone and about 6-45 hours for ethinylestradiol.
Toxicology: Preclinical safety data: In laboratory animals, the effects of drospirenone and ethinylestradiol were confined to those associated with the recognized pharmacological action. Particularly, reproduction toxicity studies revealed embryotoxic and fetotoxic effects in animals which are considered as species specific. At exposures exceeding those in users of the drospirenone and ethinylestradiol combination tablets, effects on sexual differentiation were observed in rat fetuses, but not in monkeys.
