Effect of eslicarbazepine acetate on the pharmacokinetics of a combined ethinylestradiol/levonorgestrel oral contraceptive in healthy women.

OBJECTIVE: To investigate the effect of once-daily (QD) eslicarbazepine acetate (ESL) 800 mg and 1,200 mg administration on pharmacokinetics of a combined ethinylestradiol/levonorgestrel oral contraceptive (OC) in women of childbearing potential. METHODS: Two two-way, crossover, two-period, randomized, open-label studies were performed in 20 healthy female subjects, each. In one period (ESL+OC period), subjects received ESL 800 mg QD in one study and ESL 1200 mg QD in the other study, for 15 days; concomitantly with the Day 14 ESL dose, an oral single dose of 30 µg ethinylestradiol and 150 µg levonorgestrel was administered. In the other period (OC alone), a single dose of 30 µg ethinylestradiol and 150 µg levonorgestrel was administered. Three weeks or more separated the periods. An analysis of variance (ANOVA) was used to test for differences between pharmacokinetic parameters of 30 µg ethinylestradiol and 150 µg levonorgestrel following ESL+OC and OC alone, and 90% confidence intervals (90%CI) for the ESL+OC/OC alone geometric mean ratio (GMR) were calculated. RESULTS: ESL significantly decreased the systemic exposure to both ethinylestradiol and levonorgestrel. GMR (90%CI) for AUC0-24 of ethinylestradiol were 68% (64%; 71%) following 1,200 mg ESL and 75% (71%; 79%) following 800 mg ESL. GMR (90%CI) for AUC0-24 of levonorgestrel were 76% (68%; 86%) following 1,200 mg ESL and 89% (82%; 97%) following 800 mg ESL. CONCLUSIONS: A clinically relevant dose-dependent effect of ESL administration on the pharmacokinetics of ethinylestradiol and levonorgestrel was observed. Therefore, to avoid inadvertent pregnancy, women of childbearing potential should use other adequate methods of contraception during treatment with ESL, and, in case ESL treatment is discontinued, until CYP3A4 activity returns to normal.

Contraceptive vaginal rings releasing Nestorone and ethinylestradiol: a 1-year dose-finding trial.

In a multicenter 1-year trial of contraceptive vaginal rings (rings) involving 150 women, three dose combinations of the progestin Nestorone (NES) and ethinylestradiol (EE) were compared with respect to effectiveness, safety and acceptability. Mean in vitro drug release rates for the three doses were 150 and 15, 150 and 20 and 200 and 15 microg/day of NES and EE, respectively. Each ring remained in situ for 21 days, removed for 7 days and then reinserted for a total of 13 cycles of use. We studied ring performance with respect to pregnancy and other termination events, adverse events, the extent of ovulation inhibition, serum drug levels and bleeding control. We also assessed the rings' effects on the vagina using a standardized colposcopy procedure. Seventy-two percent of the women completed the 1-year (> or = 350 days) study. In studied cycles, luteal activity (progesterone > or = 10 nmol/L) was noted in 17%, 7% and 12% of subjects with monitored cycles at the 150/15, 150/20 and 200/15 doses, respectively (p = .34). Two pregnancies occurred, both in subjects using the 200/15 microg/day ring. Breakthrough bleeding during ring use averaged about 2 days/year and breakthrough bleeding and spotting averaged about 7 days/year. In the entire trial, only two women discontinued because of bleeding problems. Medical conditions, chiefly vaginal problems, personal reasons and device loss or repeated expulsion were the principal reasons given for study discontinuation. Vaginal and cervical colposcopy, conducted with standardized techniques and standardized interpretations, revealed no elevated event incidence attributable to ring use. Clinical performance and adverse event profiles indicate that each of these 1-year NES/EE rings, used on a 21-day-in and 7-day-out regimen, provided women effective, acceptable and safe long-acting contraception under their own control.

Use of progestogen-only contraceptives/medications and lipid parameters in women age 40 to 42 years: results of a population-based cross-sectional Norwegian Survey.

This population-based cross-sectional study assessed lipid and lipoprotein parameters in women using progestogen-only contraceptives or medications and in those using no hormones. Unselected women about age 40 to 42 years were invited, and the participation rate was 65.6%. A total of 30,636 women were premenopausal, not pregnant, and used either a progestogen [n = 3000, including 2463 users of a intrauterine device (IUD) with levonorgestrel 20 microg/24 h] or no sex hormones. Those using the hormone-releasing IUD reported better health and a healthier lifestyle than nonusers of hormones, while women using depot medroxyprogesterone acetate had a less healthy lifestyle. Compared with nonusers of hormones, users of a levonorgestrel IUD were more likely to have high density lipoprotein (HDL)-cholesterol concentrations < or =1.1 mmol/L (odds ratio 1.4; 95% CI 1.2-1.5), while users of oral norethisterone or lynestrenol, or depot medroxyprogesterone acetate had a doubled to tripled risk of low HDL-cholesterol concentrations. Use of the IUD with levonorgestrel was also linked with a decreased risk of high serum triglycerides and of high non-HDL-cholesterol concentrations and a total/HDL-cholesterol ratio similar to that of nonusers of hormones.

Prodrugs: advantage or disadvantage?

Our knowledge of the peculiarities of prohormones is rather limited, both pharmacologically and clinically. Generalizations cannot be made except that the lapse of time until peak blood values of the active drug have been reached are always greater after intake of the prodrug than after intake of the drug. This finding is presumably of no clinical importance. If pharmacokinetic differences are limited to the phase of distribution, bioequivalence may be assumed. If, on the other hand, the area under the curve during the elimination phase is smaller for the prodrug than for the drug, the potency of the former should be decreased. A shift in the spectrum of endocrine actions as a result of the biotransformation of the prodrug into the active drug is rather the exception than the rule, and so is a change in side effects. If there are major differences in this respect, metabolic pathways in addition to those leading to the respective active drug must also be taken into consideration.

Radioimmunological determination of levonorgestrel and ethinylestradiol.

A sensitive and specific radioimmunoassay for ethinylestradiol (EE2) and levonorgestrel (LN) has been developed. Antisera were raised in rabbits after injection of EE2-6-carboxymethyloxime-aminocaproic acid and LN-3-carboxy-methyloxime linked to bovine serum albumin. The sensitivity of immunoassay was 15 pg/ml for EE2 and 10 pg/ml for LN. The cross-reactions showed a high specificity of the assay, and the accuracy and precision of this method satisfied the requirements for the investigation of pharmacokinetics. With this assay, although the recovery of the assay was not very high (the coefficient of variation 14.02% for EE2 and 10.27% for LN) when used to analyse diethylether extracts of biological fluids, a microquantitative metabolite of norethisterone (NET) and norethisterone-3-oxime (NETO), EE2 analogue in incubation solution with rat hepatocytes, was satisfactorily detected. The result showed that in vitro the amount of NETO transferred to EE2 analogue was three times as much as that of NET. It is necessary to further establish the identity and activity of the analogue, but these data will be found advantageous to the research of steroid-oxime.

[Pharmacokinetics of norethindrone and lynestrenol studied by HPLC (author's transl)].

The concentration of norethindrone in plasma samples from subjects receiving norethindrone (norethisterone) and lynestrenol orally was measured by high pressure liquid chromatography (HPLC). Norethindrone is a synthetic gestagen widely used in contraceptive formulations, and lynestrenol is also a synthetic gestagen which is metabolized to norethindrone in humans. But the evaluation of plasma norethindrone levels in subjects receiving lynestrenol has not yet been reported. After the administration of norethindrone, the peak level of norethindrone in the plasma was obtained within 2h, and the peak concentration in the plasma was about 3.5 ng/ml/mg norethindrone. During a period of 2-6hs after the administration of norethindrone, the half life of norethindrone in the plasma was approximately 1.8h, and during the period of 6-24hs, half life was variable. On the other hand, after the administration of lynestrenol, the peak level of norethindrone in the plasma was obtained within 4h, and the peak concentration of norethindrone was about 1.9 ng/ml/mg lynestrenol. During a period of 4-12hs, the half life of norethindrone was about 2.5h. The peak of the norethindrone level after the administration of lynestrenol was lower and appeared later than that after the administration of the same dose of norethindrone. Norethindrone in plasma in subjects receiving lynestrenol could be measured for a longer period than in those receiving the same dose of norethindrone. These results suggest that lynestrenol is stored in fat tissue and is slowly metabolized to norethindrone.

PIP: The concentration of norethindrone in plasma samples from subjects receiving norethindrone (norethisterone) and lynestrenol orally was measured by high pressure liquid chromatography (HPLC). Norethindrone is a synthetic gestagen widely used in contraceptive formulations, and lynestrenol is also a synthetic gestagen which is metabolized to norethindrone in humans. But the evaluation of plasma norethindrone levels in subjects receiving lynestrenol has not yet been reported. After the administration of norethindrone, the peak level of norethindrone in the plasma was obtained within 2 hours, and the peak concentration in the plasma was about 3.5 ng/ml/mg norethindrone. During a period of 2-6 hours after the administration of norethindrone, the half-life of norethindrone in the plasma was approximately 1.8 hours, and during the period of 6-24 hours, half-life was variable. On the other hand, after lynestrenol administration, the peak level of norethindrone in the plasma was obtained within 4 hours, and the peak concentration of norethindrone was about 1.9 ng/ml/mg lynestrenol. During a period of 4-12 hours, the half-life of norethindrone was about 2.5 hours. The peak of norethindrone level after lynestrenol administration was lower and appeared later than that after administration of the same dose of norethindrone. Norethindrone in plasma in subjects receiving lynestrenol could be measured for a longer period than in those receiving the same dose of norethindrone. These results suggest that lynestrenol is stored in fat tissue and is slowly metabolized to norethindrone. (author's)

Metabolites of lynestrenol acetate in the bile of rats after intravenous administration; a comparison with lynestrenol.

Some aspects of the metabolism of lynestrenol acetate, an orally active contraceptive compound, were studied in female rats. Lynestrenol acetate is stable in gastric and intestinal juice in vitro. After intravenous administration of lynestrenol acetate and lynestrenol with a -14C label in the nucleus approximately 40% of the administered radioactivity was excreted in the bile within 90 min. After administration of lynestrenol acetate labelled in the ester group, 6% of the radioactivity was found in the bile. This means that the greater part of the lynestrenol acetate had lost its acetate group during the process of metabolism. There was an important difference between the autoradiograms of the thin layer patterns of post-hydrolysis extracts after administration of [4-14C]lynestrenol acetate and those after administration of [1'-14C]lynestrenol acetate and [4-14C]lynestrenol: the major metabolite of [4-14C]lynestrenol acetate did not appear on the autoradiograms of [1'--14C]lynestrenol acetate and [4-14C]lynestrenol. This indicates that lynestrenol acetate was altered in the nucleus in the presence of the acetate group. The acetate group itself was removed, either when the alterations took place, or after it had been completed. The results of IR, NMR and mass spectrometry analysis indicate the introduction of a 15alpha hydroxyl group. Results of gas-liquid chromatography and thin layer chromatography indicate that a second important metabolic is 19-nor-17alpha-pregn-20-yne-3alpha, 17beta-diol. The main conclusions are: 1. A part of the lynestrenol acetate is metabolized and excreted in the bile, the acetate group still being present. 2. Lynestrenol acetate is to some extent metabolized via another pathway than lynestrenol. This indicates that esterification of a steroid can lead to deviation from the metabolic pathway of the free original steroid.

PIP: The metabolism of lynestrenol acetate (LA), an oral contraceptive, w as studied in female rats. LA is stable in gastric and intestinal juice in vitro, and is partly absorbed unchanged after oral administration. 40% of the radioactivity is excreted in the bile within 90 minutes, when labelled in the nucleus. Administration of LA labelled in the acetate group resulted in only 6% of the radioactivity in the bile, indicating that most of LA lost the acetate group during metabolism. Complex formation with silver shows that more than 80% of the metabolites of LA still contained the 17 alpha-ethinyl group. Thin layer analysis revealed that the major metabolite of (4 carbon-14)LA did not appear in the autoradiograms of (1" carbon-14)LA or (4 carbon-14)L. LA seems to be altered in the nucleus in the presence of the acetate group. IR, NMR and mas spectrophotometric analysis indicate the introduction of a 15 alpha hydroxyl group. A second major metabolite of LA and L seems to be 19-nor-17 alpha-pregn-20-yne-3 alpha, 17 beta-diol. These results indicate that esterification of a steroid can lead to alteration in the metabolic pathway of the free steroid.

Metabolism of 4-14C lynestrenol in Thai women.

PIP: The metabolism of 4-14-carbon lynestrenol was studied in Thai women, and the results were compared with a similar study of European women. The half-lives of radioactivity in plasma and urine, and the levels of urinary radioactivity found in free, sulphate, and acid-hydrolyzed fractions were similar to those reported in the European study. The levels of radioactivity observed in enzyme-hydrolyzed urinary extracts were significantly lower among Thai women (p=.01), though the difference was probably due to the use of a different enzyme prepararation. The chromatographic mobilities of free and enzyme-hydrolyzed urinary extracts were similar for both groups, though the levels for the sulphate fractions were so variable in the Thai group that they defied comparison. The results indicate that the metabolism of lynestrenol in European and Thai women is similar, and that the observed differences are unlikely to have biological significance.^ieng