Release of 19-nor-testosterone type of contraceptive steroids through different drug delivery systems into serum and breast milk of lactating women

Toddywalla, Villi S.; Mehta, Suman; Virkar, Katayun; Saxena, B.N.

doi:10.1016/0010-7824(80)90002-5

Cited by 26 publications

(7 citation statements)

References 4 publications

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“…Milk to plasma or serum concentration ratios of about 0.1-0.34 have been reported for norethisterone and for levonorgestrel after single or repeated oral administration of different doses of the drug, either alone or in combination with EE. 7,11,12 The corresponding ratios following oral administration of cyproterone acetate 13 and megestrol acetate 14 were reported to be about 0.36 and 0.8, respectively; however, with a large interindividual variation observed in all studies, which was not seen in this study. A similar variability emerged when the milk to plasma or serum ratios were calculated based on AUC data.…”

Section: Discussioncontrasting

confidence: 76%

“…The average drospirenone concentration in breast milk over the 24-h period ranged from 1.90 to 19.22 ng/mL, with an average value of 5.60 ± 4.51 ng/mL assuming that an average daily intake of breast milk by an infant is 800 mL, 7 the total quantity of drospirenone passing to breast milk is 4478 ng during 24 h after the last dose of single repeat daily administration of drospirenone.…”

Section: Resultsmentioning

confidence: 99%

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A single-arm study to evaluate the transfer of drospirenone to breast milk after reaching steady state, following oral administration of 4 mg drospirenone in healthy lactating female volunteers

Melka¹,

Kask²,

Colli

et al. 2020

Womens Health (Lond Engl)

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Objective: The primary objective of this trial was to assess the transfer of drospirenone to breast milk after daily administration of an oral test preparation containing 4 mg of drospirenone at the steady state. The secondary objective of the trial was to assess safety based on clinical and laboratory measurements and reporting of adverse events and/or adverse drug reactions. Patients and Methods: This was an open label, non-comparative single-center study. Drospirenone 4 mg per day was the first postpartum contraceptive for the study participants who were no longer breastfeeding yet were still lactating. It was administered for 7 days to achieve steady-state concentration. All participants were volunteers who planned to use oral contraceptives as their family planning method in the future. Results: Twelve volunteers completed the trial according to the protocol, and the samples of all 12 study completers were analyzed. The average concentration–time curve of drospirenone in plasma 24 h after the administration of the last dose (area under the curve (0–24 h)) was 635.33 ng h/mL and 120 h after the single repeated dose administration (area under the curve (0–120 h)) was 1180.57 ng h/mL, respectively. The average Cmax was 48.64 ng/mL. The average concentration–time curve of drospirenone in milk 24 h after the administration of the last dose (area under the curve (0–24 h)) was 134.35 ng h/mL and 120 h after the single repeated dose administration (area under the curve (0–120 h)) was 227.17 ng h/mL, respectively. The average Cmax was 10.34 ng/mL. Conclusion: On average, 18.13% of plasma drospirenone made it to breast milk and the highest concentration of drospirenone in breast milk was 17.55% of that in plasma. The total quantity of drospirenone passing to breast milk is on average 4478 ng during a 24-h period representing 0.11% of the maternal daily dose. Thus, at the recommended doses, no effects on breastfed newborns/infants are anticipated with drospirenone 4 mg.

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Section: Discussioncontrasting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

A single-arm study to evaluate the transfer of drospirenone to breast milk after reaching steady state, following oral administration of 4 mg drospirenone in healthy lactating female volunteers

Melka¹,

Kask²,

Colli

et al. 2020

Womens Health (Lond Engl)

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“…(1977a) found in 15 women that the plasma to milk ratio was 100: 15. Almost identical amounts of lcvonorgestrel in milk were reported by Toddywalla et al (1980) but the women were receiving a rather larger dose of 150/otg daily. Concentrations of levonorgestrel in the infants were always less than 120 pg/ml and there was no evidence that levonorgestrel accumulated in the infant's plasma.…”

Section: Levonorgestrel In Breast Milk and Other Tissuesmentioning

confidence: 68%

Clinical Pharmacokinetics of Oral Contraceptive Steroids

Orme

Back

Breckenridge

1983

Clinical Pharmacokinetics

159

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Oral contraceptive steroids are of 2 types: oestrogens, of which ethinyloestradiol is the most important, and progestagens, of which levonorgestrel and norethisterone are the most commonly used. All these steroids can be measured by a number of analytical techniques but there is little doubt that radioimmunoassay is the most convenient. All. the steroids are well absorbed in humans but while levonorgestrel is completely bioavailable, norethisterone has an average bioavailability of 70%. Ethinyloestradiol, too, is subject to presystemic metabolism with a mean bioavailability of 40 to 45%. The main site of presystemic metabolism is the gut wall, with the production of ethinyloestradiol sulphate. The progestagens norethynodrel, ethynodiol diacetate and lynoestrenol are quantitatively metabolised to norethisterone.The pharmacokinetics of the contraceptive steroids are best described by a 2-compartment open model. The terminal plasma half-life of levonorgestrel varies from 11 to 45 hours and of norethisterone from 5 to 14 hours. The Ii-phase half-life of ethinyloestradiol varies from 6 to 20 hours. The apparent volume of distribution of these contraceptive steroids (after intravenous administration) is between 1.5 and 4.3 Llkg. During long term treatment with oral contraceptive steroids, steady-state plasma concentrations of ethinyloestradiol (24 hours after administration) are between 10 and 200 pg/m!. Plasma concentrations of norethisterone and levonorgestrel at steady-state are higher than predicted from the single-dose kinetics because of enhanced binding of the progestagens following the induction of sex hormone binding globulin (SHBG) by ethinyloestradiol. Concentrations are in the range of 1.6 to 15.2 nglml for norethisterone and 0.8 to 4.5 nglml for levonorgestrel.All the contraceptive steroids are bound to proteins in plasma. Ethinyloestradiol is 97 to 98% bound to plasma albumin. The progestagens are bound both to albumin (levonorgestrel 93 to 95%; norethisterone 79 to 80%) and more specifically to SHBG. The binding capacity of SHBG can be enhanced by treatment with ethinyloestradiol or with more conventional enzyme-inducing drugs such as phenobarbitone, carbamazepine or rifampicin.Norethisterone and levonorgestrel are chiefly metabolised by reduction in the A ring and this is followed by conjugation with glucuronide or sulphate. The metabolism of levonorgestrel is stereoselective. Ethinyloestradiol is primarily hydroxylated at the 2 position but a wide variety of hydroxylated and methylated metabolites are formed and these are present both free and as glucuronide and sulphate conjugates. Ethinyloestradiol is conjugated directly at the 3 position (unlike the progestagens) and thus is liable to enterohepatic recirculation. Ethinyloestradiol sulphate concentrations in plasma are many times higher than that of the unchanged drug.

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“…The transfer of NET and NG administered to the mother, either orally (NET 350 Izg/ NG 50 ~tg) or through biodegradable implants (25 mg NET/NG), indicated that regardless of the route of administration approximately 10% of the NET/NG in the maternal circulation was transferred to her milk [18]. Other investigators [13,19] have also reported a transfer percentage ranging from 15 to 18.…”

Section: Transfer Of Net/ng To Breast Milkmentioning

confidence: 99%

Low-dose progestogen contraception and the nursing mother

et al. 1995

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Breast feeding, though an important and efficient contraceptive method, suffers from one major limitation: the contraceptive protection it offers the nursing mother ends abruptly without giving any physical indication of the return of fertility. Barrier methods and progesterone-only hormonal contraceptives, either in the oral, implant or injectable form, appear to be the primary contraceptive alternative for the nursing mother today. They neither adversely affect lactation, nor does the minute quantity of progesterone (NET or LNG) transferred to the infant affect its growth and physical well-being. Puerperal insertion of IUD carries an inherent risk of pelvic inflammatory disease, high expulsion rates and menorrhagia, once menses resume. Combination contraceptives affect both the quality and quantity of breastmilk; hence they are not recommended. Sterilization is a permanent method and therefore useful only when the family has been completed.

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Release of 19-nor-testosterone type of contraceptive steroids through different drug delivery systems into serum and breast milk of lactating women

Cited by 26 publications

References 4 publications

A single-arm study to evaluate the transfer of drospirenone to breast milk after reaching steady state, following oral administration of 4 mg drospirenone in healthy lactating female volunteers

A single-arm study to evaluate the transfer of drospirenone to breast milk after reaching steady state, following oral administration of 4 mg drospirenone in healthy lactating female volunteers

Clinical Pharmacokinetics of Oral Contraceptive Steroids

Low-dose progestogen contraception and the nursing mother

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