Minimal androgenic activity of a new oral contraceptive containing norethindrone acetate and graduated doses of ethinyl estradiol.

The pharmacokinetics and androgenic activity of Estrostep, a new oral contraceptive providing low-dose estrogen in a graduated sequence with a constant dose of progestin, were characterized in an open-label, nonrandomized study in 17 normally cycling women treated for three cycles with Estrostep. Women received 1 mg of norethindrone acetate daily combined with 20 microg of ethinyl estradiol daily for the first 5 days (1/20), 30 microg of ethinyl estradiol daily for the next 7 days (1/30), and 35 microg of ethinyl estradiol daily for 9 days (1/35). No medication was given for 7 days in each cycle to allow for withdrawal bleeding. Serial blood samples for the measurement of ethinyl estradiol and norethindrone concentrations were collected on days 5, 12, and 21 of the third treatment cycle for the 1/20, 1/30, and 1/35 dose, respectively. Sex hormone-binding globulin (SHBG) and free testosterone were measured at baseline, on day 1 of cycles 2 and 3 (SHBG only), and on days 5, 12, and 21 of cycle 3. Mean steady-state plasma ethinyl estradiol and norethindrone concentrations increased over cycle 3. The increases in ethinyl estradiol concentrations were proportional to dose. The increases in norethindrone concentrations were related to ethinyl estradiol-dependent increases in SHBG concentrations, which were 218%, 253%, and 296% of baseline values on days 5, 12, and 21, respectively. Mean plasma free testosterone concentrations decreased 47%, 60%, and 64% below baseline on days 5, 12, and 21 of cycle 3, respectively. Graduated ethinyl estradiol doses combined with a constant norethindrone acetate dose progressively increase SHBG and decrease free testosterone, which overrides any theoretic concerns of androgenic activity of norethindrone acetate. Although true androgenic activity can be determined only by assessing endpoints such as acne, hirsutism, and lipids in large controlled trials, the observed changes in circulating SHBG and free testosterone concentrations indicate that Estrostep has little, if any, intrinsic androgenic activity.

Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion.

The effect of atovarstatin on digoxin pharmacokinetics was assessed in 24 healthy volunteers in two studies. Subjects received 0.25 mg digoxin daily for 20 days, administered alone for the first 10 days and concomitantly with 10 mg or 80 mg atorvastatin for the last 10 days. Mean steady-state plasma digoxin concentrations were unchanged by administration of 10 mg atorvastatin. Mean steady-state plasma digoxin concentrations following administration of digoxin with 80 mg atorvastatin were slightly higher than concentrations following administration of digoxin alone, resulting in 20% and 15% higher Cmax and AUC(0-24) values, respectively. Since tmax and renal clearance were not significantly affected, the results are consistent with an increase in the extent of digoxin absorption in the presence of atorvastatin. Digoxin is known to undergo intestinal secretion mediated by P-glycoprotein. Since atorvastatin is a CYP3A4 substrate and many CYP3A4 substrates are also substrates for P-glycoprotein transport, the influence of atorvastatin and its metabolites on P-glycoprotein-mediated digoxin transport in monolayers of the human colon carcinoma (Caco-2) cell line was investigated. In this model system, atorvastatin exhibited efflux or secretion kinetics with a K(m) of 110 microM. Atorvastatin (100 microM) inhibited digoxin secretion (transport from the basolateral to apical aspect of the monolayer) by 58%, equivalent to the extent of inhibition observed with verapamil, a known inhibitor of P-glycoprotein transport. Thus, the increase in steady-state digoxin concentrations produced by 80 mg atorvastatin coadministration may result from inhibition of digoxin secretion into the intestinal lumen.

Characterization of a 7 day 17 beta-estradiol transdermal delivery system: pharmacokinetics in healthy postmenopausal women.

To assess the delivery characteristics of a new 7 day 17 beta-estradiol transdermal delivery system (TDS), estradiol and estrone pharmacokinetics were evaluated following a single 7 d application of one TDS or two TDSs in 24 healthy, postmenopausal women in a nonblind, randomized, two-period crossover study. Serial blood samples and total urine output were collected before (baseline measurement of endogenous hormone) and during TDS application, and for 24 h (urine) or 72 h (blood) following TDS removal. Serum was assayed for estradiol and estrone by a validated radioimmunoassay (RIA) method. The combined amounts of estradiol and its conjugates, and estrone and its conjugates in urine were determined by validated RIA methods. Overall, one or two estradiol TDSs were well tolerated by healthy, postmenopausal female volunteers. Estradiol absorption from the TDS was characterized by a zero-order process and was dose proportional, resulting in average steady-state serum estradiol concentrations of 16 and 33 pg mL-1 above baseline during the 7 d application of one and two TDSs, respectively. Parallel but smaller increases in serum estrone concentrations were observed, resulting in an increase in the serum estradiol/estrone concentration ratio from approximately 0.2 at baseline to median values of 0.64 and 0.88 during application of one and two TDSs, respectively. The 7 day 17 beta-estradiol TDS delivered a nominal estradiol dose of 0.02 mg/24 h during the intended wear period.