After absorption of the oral emergency contraceptive preparation, levonorgestrel is conjugated and forms a large number of sulfate conjugates. In addition, glucuronide conjugates have been identified in the plasma. High levels of conjugated and unconjugated 3α, 5β-tetrahydrolevonorgestrel are found in the plasma. The entire metabolic pathway for levonorgestrel has not been studied, however, 16β-hydroxylation is one pathway that has been identified. Small quantities of 3α, 5α tetrahydrolevonorgestrel and 16βhydroxylevonorgestrel are also formed. No active metabolites have been identified. The rate of metabolism may be considerably different according to the patient and may explain a wide variation in levonorgestrel clearance. Liver CYP3A4 and CYP3A5 hepatic enzymes are reported to be involved in the metabolism of levonorgestrel.
(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.
Binds to the progesterone and estrogen receptors. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins like levonorgestrel will slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH (luteinizing hormone) surge.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 用于研究药物诱导肝损伤的FDA批准药物标签，药物发现今日，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按在人类中发展药物诱导肝损伤风险排名的最大参考药物清单。药物发现今日2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
口服左炔诺孕酮在小肠被吸收，而通过宫内节育器（IUD）给药的左炔诺孕酮则被子宫内膜吸收。当左炔诺孕酮作为皮下植入剂植入时，它立即被组织间液吸收。植入皮下植入剂后，左炔诺孕酮的Cmax在2-3天内达到。根据一项参考资料，单次口服0.75毫克左炔诺孕酮后，Cmax在给药后一小时内达到。在一项药代动力学研究中，正常体重指数（BMI）的女性和被认为是肥胖（BMI>30）的女性服用1.5毫克左炔诺孕酮后，平均Cmax分别为16.2 ng/mL和10.5 ng/mL。正常BMI组的Tmax为2小时，而BMI增加的患者为2.5小时。左炔诺孕酮的生物利用度接近100%。正常BMI患者的平均AUC较高，为360.1 h × ng/mL，而肥胖患者组的AUC范围为197.28至208.1 h × ng/mL。肥胖可能会降低左炔诺孕酮在避孕中的效果。
Orally administered levonorgestrel is absorbed in the gastrointestinal tract while levonorgestrel administered through an IUD device is absorbed in the endometrium. Levonorgestrel is absorbed immediately in the interstitial fluids when it is inserted as a subdermal implant. After insertion of the subdermal implant, the Cmax of levonorgestrel is attained within 2-3 days.The Cmax following one dose of 0.75 mg of oral levonorgestrel is reached within the hour after administration, according to one reference. In a pharmacokinetic study of 1.5 mg of levonorgestrel in women with a normal BMI and those considered to be obese (BMI>30), mean Cmax was found to be 16.2 ng/mL and 10.5 ng/mL respectively. Tmax was found to be 2 hours for those with normal BMI and 2.5 hours for patients with increased BMI. The bioavailability of levonorgestrel approaches 100%. Mean AUC has been shown to be higher in patients with a normal BMI, measuring at 360.1 h × ng/mL versus a range of 197.28 to 208.1 h × ng/mL in an obese group of patients. Obesity may contribute to decreased efficacy of levonorgestrel in contraception.
Approximately 45% of an oral levonorgestrel dose and its conjugated or sulfate metabolites are found to be excreted in the urine. Approximately 32% of an orally ingested dose is found excreted in feces, primarily in the form of glucuronide conjugates of levonorgestrel.
One pharmacokinetic study determined a mean steady-state volume of distribution of 1.5 mg of levonorgestrel to be 162.2 L in those with normal BMI and in the range of 404.7 L to 466.4 L in obese patients with a body mass index of at least 30. Mean volume of distribution in 16 patients receiving 0.75 mg of levonorgestrel in another pharmacokinetic study was 260 L. The Plan B one-step FDA label reports an apparent volume of distribution of 1.8 L/kg.
Clearance was found to 4.8 L/h in healthy female volunteers with a normal BMI, and 7.70-8.51 L/h in obese patients after a single 1.5 mg dose. After a 0.75 mg dose of levonorgestrel in 16 patients in another pharmacokinetic study, mean clearance was calculated at 7.06 L/h. Following levonorgestrel implant removal, the serum concentration falls below 100 pg/mL within the first 96 hours and further falls below the sensitivity of detection within the range of 5 days to 2 weeks.
Norgestrel is absorbed from the gastrointestinal tract, metabolised by the liver and excreted in the urine and faeces as glucuronide and sulphate conjugates.
