Volina Mechanism of Action

Pharmacotherapeutic group: Sex hormones and modulators of the genital system; Progestogens and estrogens, fixed combinations. ATC code: G03AA12.
Pharmacology: Pharmacodynamics: Mechanism of action: The contraceptive effect of Volina is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the endometrium.
Volina is a combined oral contraceptive with ethinylestradiol and the progestogen drospirenone. In a therapeutic dosage, drospirenone also possesses antiandrogenic and mild antimineralocorticoid properties. It has no estrogenic, glucocorticoid and antiglucocorticoid activity. This gives drospirenone a pharmacological profile closely resembling the natural hormone progesterone.
Pharmacokinetics: Drospirenone: Absorption: Orally administered drospirenone is rapidly and almost completely absorbed. Maximum concentrations of the active substance in serum of about 38 ng/ml are reached at about 1-2 h after single ingestion. Bioavailability of drospirenone is between 76 and 85%. Concomitant ingestion of food has no influence on the bioavailability of drospirenone.
Distribution: After oral administration, serum drospirenone levels decrease in two phases, with terminal half-lives of 31 h. Drospirenone is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). Only 3-5% of the total serum concentrations of the active substance are present as free steroid. The ethinylestradiol-induced increase in SHBG does not influence the serum protein binding of drospirenone. The mean apparent volume of distribution of drospirenone is 3.7±1.2 l/kg.
Biotransformation: Drospirenone is extensively metabolised after oral administration. The major metabolites in the plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulfate, both of which are formed without involvement of the P450 system. Drospirenone is metabolized to a minor extent by cytochrome P450 3A4 and has demonstrated a capacity to inhibit this enzyme and cytochrome P450 1A1, cytochrome P450 2C9 and cytochrome P450 2C19 in vitro.
Elimination: The metabolic clearance rate of drospirenone in serum is 1.5±0.2 ml/min/kg. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the feces and urine at an excretion ratio of about 1.2 to 1.4. The half-life of metabolite excretion with the urine and feces is about 40 h.
Steady-state conditions: During a treatment cycle, the maximum steady-state concentrations of drospirenone in serum of about 70 ng/ml are reached after about 8 days of treatment. Serum drospirenone levels accumulated by a factor of about 3 as a consequence of the ratio of terminal half-life and dosing interval.
Special populations: Effect of renal impairment: Drospirenone treatment was also well tolerated by women with mild and moderate renal impairment. Drospirenone treatment did not show any clinically significant effect on serum potassium concentration.
Effect of hepatic impairment: Drospirenone is well tolerated in patients with mild or moderate hepatic impairment (Child-Pugh B).
Ethnic groups: No clinically relevant differences in the pharmacokinetics of drospirenone or ethinylestradiol between Japanese and Caucasian women have been observed.
Ethinylestradiol: Absorption: Ethinylestradiol is rapidly and completely absorbed after ingestion. After administration of 30 μg, peak plasma concentrations of 100 pg/ml are reached 1-2 hours after ingestion. Ethinylestradiol undergoes an extensive first-pass effect, which displays great inter-individual variation. The absolute bioavailability is approx. 45%.
Distribution: Ethinylestradiol has an apparent volume of distribution of 5 l/kg and binding to plasma proteins is approx. 98%. Ethinylestradiol induces the hepatic synthesis of SHBG and CBG. During treatment with 30 μg ethinylestradiol the plasma concentration of SHBG increases from 70 to about 350 nmol/l. Ethinylestradiol passes in small amounts into breast milk (0.02% of the dose).
Biotransformation: Ethinylestradiol is metabolised completely (metabolic plasma clearance 5 ml/min/kg).
Elimination: Ethinylestradiol is not excreted in unchanged form to any significant extent. The metabolites of ethinylestradiol are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day. The elimination half-life is 20 hours.
Steady-state conditions: Steady-state conditions are reached during the second half of a treatment cycle and serum levels of ethinylestradiol accumulated by a factor of about 1.4 to 2.1.