(14)C-Norgestrel was administered to seven human subjects and 43% of dose was excreted in the urine within 5 days ... Enzymic hydrolysis released only 32% of the urinary radioactivity and a further 25% was excreted as sulphate conjugates. The metabolites excreted in the urine were much less polar than those following the administration of the related compounds, norethisterone or lynestrenol. The 3alphaOH,5beta and 3betaOH,5beta isomers of the tetrahydronorgestrel (13beta-ethyl-17alpha-ethynyl-5 beta-gonane-3alpha,17beta-diol) were isolated from urine and identified by mass spectrometry and thin-layer and gas-liquid chromatography. Plasma radioactivity decreased more rapidly than after the administration of norethisterone and lynestrenol. About 2% of the administered dose was converted to acidic compounds. There was no apparent difference in the rate of excretion of radioactivity or in the metabolites after either oral or intravenous administration of norgestrel.
The comparative metabolism of dl-, d-, and l-norgestrel was investigated in African Green Monkeys (Cercopithecus aethiops). Total (14)C excretion in urine after a single oral dose of (14)C-dl-norgestrel (1 mg/kg) was significantly higher (51.4 +/- 5.0%) than that observed after administration of the d-enantiomer (37.5 +/- 5.4%) but not the l-enantiomer (44.2 +/- 8.9%). In all cases, the major part of the urinary radioactivity was present in a free fraction (48-62%), while an additional 13-27% was released by beta-glucuronidase preparations. No sulfate conjugates were detected. At least one major (16beta-hydroxylation) and one minor (16alpha-hydroxylation) metabolic pathway were stereoselective, i.e., they are operative with the I-but not the d-enantiomer. Three metabolites, 16beta-hydroxynorgestrel, 16alpha-hydroxynorgestrel, and 16-hydroxytetrahydronorgestrel (believed to be 16beta) were only detected in urine samples obtained from (14)C-dland -l-norgestrel-dosed animals. Following (14)C-d-norgestrel administration, 3alpha, 5beta-tetrahydronorgestrel was found to be the major urinary metabolite. These observations are compared with those reported earlier on the urinary metabolites of dl-norgestrel in women.
The in vitro metabolism of stereo-isomers (d, l and the racemic mixture dl) of norgestrel by a microsomal fraction from rabbit liver was investigated. The metabolism of the biologically active l-norgestrel was more rapid than that of d-norgestrel (sic.) which is biologically inactive. This was mainly due to the more ready conversion of l-norgestrel to ring-A reduced metabolites. There was no difference between the two isomers in respect of the amount undergoing hydroxylation; about 40% of each isomer was converted to hydroxylated metabolites after 30 min incubation. However, there were differences between the isomers, l-norgestrel being converted mainly to the 16beta-hydroxysteroid and d-norgestrel to the 16alpha-hydroxysteroid. Similar amounts of both isomers were hydroxylated at C-6. The metabolism of the racemic mixture was intermediate between that of the d and l isomers.
The rates of metabolism of synthetic gestagens derived from 19-nortestosterone by rabbit liver tissue in vitro were compared. Over a period of 1 hr norethisterone was metabolized as rapidly as 19-nortestosterone whereas d-norgestrel and lynestrenol were metabolized at a slightly lower rate. Less than 5% of l-norgestrel was metabolized. In all cases the reaction product was the tetrahydrosteroid. Lynestrenol was metabolised through norethisterone. Skeletal muscle, lung and small intestine also metabolized norethisterone and d-norgestrel but at a slower rate than liver tissue. Small amounts of norethisterone were metabolized by adipose tissue but heart and spleen were inactive. Lynestrenol and l-norgestrel were not metabolized by any of the extra-hepatic tissues studied.
In vitro studies were conducted on the metabolism of 3 steroids used in OCs (oral contraceptives) by small pieces of human jejunal mucosa. This was done because the gastrointestinal mucosa of humans is known to metabolize a number of drugs. Almost 40% of the ethinyl estradiol, 9.8% of the levonorgestrel, and 7% of the mestranol were metabolized after incubation. All these metabolic responses were significantly different from those in the control groups. Results of the study show that the metabolism of the ethinyl estradiol was related to the weight of the tissue used. These results are consistent with the known marked 1st pass effect of ethinyl estradiol. Norgestrel, known to have little or no 1st pass effect, did not show a high rate of gut metabolism. Under the experimental conditions employed, no Phase 1 metabolism of either ethinyl estradiol or levonorgestrel was apparent.
◉ Summary of Use during Lactation:This record contains information specific to oral levonorgestrel used alone for contraception. Those with an interest in a combination oral contraceptive should consult the record entitled, Contraceptives, Oral, Combined.
Although nonhormonal methods are preferred during breastfeeding, progestin-only contraceptives such as levonorgestrel are considered the hormonal contraceptives of choice during lactation. Fair quality evidence indicates that levonorgestrel does not adversely affect the composition of milk, the growth and development of the infant or the milk supply. Expert opinion holds that the risks of progestin-only contraceptive products usually are acceptable for nursing mothers at any time postpartum. Some evidence indicates that progestin-only contraceptives may offer protection against bone mineral density loss during lactation, or at least do not exacerbate it. A large percentage of women who planned to breastfeed discontinued oral progestin-only contraceptives by 3 months postpartum and progestin-only contraceptives often result in rapid repeat pregnancy.
After use of levonorgestrel as a postcoital contraceptive, nursing can resume 3 to 4 hours after the dose (or after each dose if the two-dose method is used). Postcoital levonorgestrel appears to have no long-term adverse effects on breastfeeding or the infant.
◉ Effects in Breastfed Infants:One study found serum thyroid stimulating hormone levels to be lower in the infants exposed to levonorgestrel than in control infants.
A nonrandomized trial compared 250 breastfed infants whose mothers received 30 mcg daily of oral levonorgestrel initiated 7 days postpartum to 250 infants whose mothers received nonhormonal contraception. No differences in height and weight gain were seen during the 9-month study period between the 2 groups.
Multicenter, nonrandomized studies followed infants whose mothers received levonorgestrel contraception during breastfeeding, either as oral tablets of 37.5 mcg daily (n = 246) or as Norplant (n = 453). No adverse effects on infant growth through the first year were found in comparison to standard measurements.
In a cohort study of 71 nursing women who took levonorgestrel as a postcoital contraceptive, none noticed any adverse effect in their infants.
In a cohort study, breastfed infants of women (n = 100) who used at least one dose of levonorgestrel as a postcoital contraceptive in addition to the lactational-amenorrhea method (LAM) of birth control were compared to infants whose mothers used LAM only (n = 100). No statistically significant differences were found between the groups in weight, length, head circumference, chest circumference, and mid-arm circumference at 3 and 6 months postpartum, nor in the Denver Developmental Screening Test results at 6 months postpartum.
◉ Effects on Lactation and Breastmilk:Among a cohort study of 71 women who took levonorgestrel as a postcoital contraceptive during nursing, none reported any obvious decrease in milk supply after the drug was used.
A study of 1158 postpartum randomized women using the lactational amenorrhea method (LAM) for birth control randomized to be given levonorgestrel as a postcoital contraceptive or given nothing. No difference in the duration of breastfeeding was found between women who used the levonorgestrel and those who did not.
In a nonrandomized, nonblinded study comparing women who were breastfeeding at discharge, 102 postpartum women received depot medroxyprogesterone acetate (dosage not stated) in the early postpartum period (average 51.9 hours postpartum; range 6.25 to 132 hours), 181 received another progestin-only contraceptive and 138 used nonhormonal contraception. No differences in breastfeeding rates were seen at 2 and 6 weeks, but women receiving any hormonal contraceptive were breastfeeding at a lower rate (72.1% vs 77.6%) at 4 weeks postpartum. The authors concluded that progestin-only contraception initiated in the early postpartum period had no adverse effects on breastfeeding rates.
A study analyzed data from a prospective cohort study of U.S. women from May 2005 through June 2007. Women were followed from the third trimester of pregnancy throughout the first year postpartum. Data from the subset of women who professed that intended to breastfeed for 3 months or longer postpartum during their third trimester of pregnancy and who were using a contraceptive at 3 months postpartum were analyzed (n = 1349). Women who intended to breastfeed for at least 4 months and were taking a progestin-only oral contraceptive, such as levonorgestrel, were 3.15 times more likely to be breastfeeding (exclusive or nonexclusive) at 4 months than women who used a nonhormonal contraceptive. Women who said they would breastfeed for 3 to 4 months had 4-month breastfeeding rates equivalent to those using a nonhormonal contraceptive. These rates were much higher than those of women who were taking an estrogen-containing, combined oral contraceptive.
In a cohort study, women (n = 100) who used at least one dose of levonorgestrel as a postcoital contraceptive in addition to the lactational-amenorrhea method (LAM) of birth control were compared to mothers used LAM only (n = 100). No difference was found in the mothers' subjective opinions of their milk supplies.
The metabolism of estrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (eg phenobarbital, phenytoin, carbamazepine), and anti-infectives (eg rifampicin, rifabutin, nevirapine, efavirenz).
Phenytoin and rifampin increase the serum concentrations of sex hormone-binding globulin (SHBG); this significantly decreases the serum concentration of free drug for some progestins, which is a special concern in patients using progestins for contraception. /Progestins/
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
左炔诺孕酮通过胃肠道吸收，在肝脏代谢，并以葡萄糖醛酸和硫酸盐结合物的形式通过尿液和粪便排出。
Norgestrel is absorbed from the gastrointestinal tract, metabolised by the liver and excreted in the urine and faeces as glucuronide and sulphate conjugates.
(14)C-Norgestrel was administered to seven human subjects and 43% of dose was excreted in the urine within 5 days; the biological half-life of the radioactivity was 24 hr. Enzymic hydrolysis released only 32% of the urinary radioactivity and a further 25% was excreted as sulphate conjugates. The metabolites excreted in the urine were much less polar than those following the administration of the related compounds, norethisterone or lynestrenol. The 3alphaOH,5beta and 3betaOH,5beta isomers of the tetrahydronorgestrel (13beta-ethyl-17alpha-ethynyl-5 beta-gonane-3alpha,17beta-diol) were isolated from urine and identified by mass spectrometry and thin-layer and gas-liquid chromatography. Plasma radioactivity decreased more rapidly than after the administration of norethisterone and lynestrenol. About 2% of the administered dose was converted to acidic compounds. There was no apparent difference in the rate of excretion of radioactivity or in the metabolites after either oral or intravenous administration of norgestrel.
The binding of different synthetic steroids, used in hormonal contraception, to Sex Hormone Binding Globulin (SHBG) was studied by measuring their ability to displace tritiated testosterone from SHBG in a competitive protein binding system. Only 19-nortestosterone derivates had any significant ability to displace testosterone from SHBG, d-norgestrel (d-Ng) being the strongest displacer. Increasing the SHBG levels in women with previous constant plasma d-Ng levels increased these levels two- to sixfold. It is concluded that SHBG is the main carrier protein for d-Ng. The strong testosterone displacing activity of d-Ng might also explain androgenic side effects observed with d-Ng containig oral contraceptives.
A hydrogel which comprises polymerised moieties derivable from (i) at least one polymerisable cyclic (thio)ether and (ii) at least one hydrophilic homo- or copolymer.
一种水凝胶，包含可由 (i) 至少一种可聚合环（硫）醚和 (ii) 至少一种亲水均聚物或共聚物衍生的聚合分子。
Compositions comprising encapsulated particles
申请人：NATIONAL RESEARCH DEVELOPMENT CORPORATION
公开号：EP0076158A2
公开（公告）日：1983-04-06
A composition which comprises at least one solid or liquid particle comprising at least one active substance, the or a plurality of such particles being encapsulated by the in situ cationic (co)polymerisation thereon of at least one cationically polymerisable monomer or prepolymer.
A non-crosslinked derivative formable by reacting at least one substituted or unsubstituted, saturated or unsaturated, mono-, di- or poly-carboxy, hydroxy or mercapto hydrocarbon with at least one cyclic unsaturated (thio)ether.
A controlled release device which comprises:
(i) a hydrogel; and incorporated therewith
(ii) an active substance,
at least part of at least one surface of the device comprising (iii) a layer which is impermeable to aqueous media.
一种控释装置，包括
(i) 水凝胶；并与之结合
(ii) 一种活性物质、
(iii) 不透水介质层。
Hormone composition and use
申请人：JENCAP RESEARCH LIMITED
公开号：EP0309263A2
公开（公告）日：1989-03-29
This invention is concerned with a contraceptive formulation and a method of contraception which employs a combination of estrogen and progestin and wherein a short period of relatively dominant estrogenic activity alternates with a short period of relatively dominant progestagenic activity. The invention also concerns a hormonal replacement formulation and method for use in menopausal or castrate women which employs a similar combination of estrogen and progestin.
