Endogenous Metabolite; synthetic form of the thyroid hormone thyroxine (T4)

左旋甲状腺素治疗在体外动物模型中产生异常的子宫收缩模式[2] 甲状腺功能筛查证实，在无碘饮食下，所有大鼠都处于甲状腺功能减退状态，随后给予T4以平衡甲状腺功能减退。结果表明，甲状腺功能减退显著缩短了收缩持续时间（-17%），增加了收缩频率（+26%），而高剂量的T4增加了持续时间（+200%），降低了频率（-51%）。因此，这些结果模拟了之前在T4治疗的甲状腺功能减退孕妇的子宫组织中观察到的异常收缩模式。 结论：我们的数据表明，T4治疗会引起子宫肌层反应性的变化。因此，结合我们之前对人类子宫肌层条带的观察，应改进甲状腺功能减退症的治疗，以降低这组患者的剖腹产率[2]。

脱碘酶 (DIO) 可催化肾上腺素（皮质原）转化为活跃的肾上腺皮质，与催化肾上腺素 (TSH) 水平相对应。 DIO1和DIO2加速肾上腺皮质的激活，而DIO3则降低至不活动状态。 DIO1和DIO2的作用在垂体TSH的负反馈控制中起着至关重要的作用[1]。 L-甲状腺素钠 (T4) 和三前列腺素 (T3) 已知会影响离子通道、泵和调节特性。此外，胰岛激素已被证明会影响北极素和涉及兴奋性和收缩性的蛋白质的表达，L-胰岛素和三碘甲状腺原氨酸控制其药理调节。在为期 12 周的队列中，与传统饮食喂养的对照组相比，三碘甲状腺原氨酸和 L-甲状腺素的水平显着降低。在低剂量 L-甲状腺素治疗组中，L-甲状腺素水平有所增加，尽管三碘甲状腺原氨酸水平实际上与甲状腺中的水平相似。与未治疗的甲状腺功能减退组相比，接受高剂量 L-甲状腺素治疗的个体中三碘甲状腺原氨酸和 L-pakatin 的循环浓度显着升高，且 L-pakatin 水平与对照值相比显着升高 [2]。

生化技术[2] 根据制造商的方案，使用标准大鼠甲状腺素（T4）和T3 ELISA试剂盒进行ELISA测定。如前所述，进行了蛋白质印迹分析。

Sprague–Dawley female rats (N = 22) were used. Non-pregnant rats were divided into four groups: 1) control, 2) hypothyroidism, 3) hypothyroidism treated with low doses of Levothyroxine (T4) (20 μg/kg/day) and 4) with high doses of T4 (100 μg/kg/day). Control rats (group 1) were fed with standard diet (TD.120461, Harlan laboratories, Madison, WI) while the intervention rats were fed with iodine-free diet for 12 weeks to induce hypothyroidism (groups 2–4) which was continued for four more weeks to allow screening of hypothyroid status and T4-treatment. Food and water (iodine-free diet) were available ad libitum. The hypothyroid group treated with low (group 3) or high doses of T4 (group 4) were injected intraperitoneally every 24 h with respectively 20 μg/kg/day and 100 μg/kg/day as previously described by Medeiros. Blood samples were collected for thyroid function screening at week 12 and 16 following the initiation of either the control or iodine-free diet. Hysterectomy was performed under general anesthesia (isoflurane 2%) at the end of the treatment and the two uterine horns were placed in physiological Krebs' solution until isometric tension measurements within no more than 1 h.[2]

Absorption
Absorption of orally administered T4 from the gastrointestinal tract ranges from 40% to 80% with the majority of the levothyroxine dose absorbed from the jejunum and upper ileum. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybeans, milk, and dietary fiber. Absorption may also decrease with age. In addition, many drugs affect T4 absorption including bile acide sequestrants, sucralfate, proton pump inhibitors, and minerals such as calcium (including in yogurt and milk products), magnesium, iron, and aluminum supplements. To prevent the formation of insoluble chelates, levothyroxine should generally be taken on an empty stomach at least 2 hours before a meal and separated by at least 4 hours from any interacting agents.

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Route of Elimination
Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces. Approximately 20% of T₄ is eliminated in the stool. Urinary excretion of T₄ decreases with age.

Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA), whose capacities and affinities vary for each hormone. The higher affinity of both TBG and TBPA for T4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T4 compared to T3. Protein-bound thyroid hormones exist in reverse equilibrium with small amounts of free hormone. Only unbound hormone is metabolically active. Many drugs and physiologic conditions affect the binding of thyroid hormones to serum proteins. Thyroid hormones do not readily cross the placental barrier. NIH; DailyMed. Current Medication Information for Synthroid (Levothyroxine Sodium) Tablet (Updated: December 2015). Available from, as of April 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=665c1eab-2649-498b-8da8-b15b3b743a21

Levothyroxine Sodium for Injection is administered via the intravenous route. Following administration, the synthetic levothyroxine cannot be distinguished from the natural hormone that is secreted endogenously. NIH; DailyMed. Current Medication Information for Levothyroxine Sodium (Levothyroxine Sodium) Anhydrous Injection, Powder, Lyophilized, For Solution (Updated: March 2015). Available from, as of April 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f88f44d8-2f18-4155-9d78-6323d19fbafe

Absorption of orally administered T4 from the gastrointestinal (GI) tract ranges from 40% to 80%. The majority of the levothyroxine dose is absorbed from the jejunum and upper ileum. The relative bioavailability of Synthroid tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 93%. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybean infant formula. Dietary fiber decreases bioavailability of T4. Absorption may also decrease with age. In addition, many drugs and foods affect T4 absorption. NIH; DailyMed. Current Medication Information for Synthroid (Levothyroxine Sodium) Tablet (Updated: December 2015). Available from, as of April 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=665c1eab-2649-498b-8da8-b15b3b743a21

Levothyroxine is variably absorbed from the GI tract (range: 40-80%). In animals, levothyroxine is absorbed in the proximal and middle jejunum; the drug is not absorbed from the stomach or distal colon and little, if any, absorption occurs in the duodenum. Studies in humans indicate that levothyroxine is absorbed from the jejunum and ileum and some absorption also occurs in the duodenum. The degree of absorption of levothyroxine from the GI tract depends on the product formulation and type of intestinal contents, including plasma protein and soluble dietary factors that may bind thyroid hormone and make it unavailable for diffusion. In addition, concurrent oral administration of infant soybean formula, soybean flour, cotton seed meal, walnuts, foods containing large amounts of fiber, ferrous sulfate, antacids, sucralfate, calcium carbonate, cation-exchange resins (e.g., sodium polystyrene sulfonate), simethicone, or bile acid sequestrants may decrease absorption of levothyroxine. The extent of levothyroxine absorption is increased in the fasting state and decreased in malabsorption states (e.g., sprue); absorption also may decrease with age. American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 3230

For more Absorption, Distribution and Excretion (Complete) data for LEVOTHYROXINE (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Approximately 70% of secreted T4 is deiodinated to equal amounts of T3 and reverse triiodothyronine (rT3), which is calorigenically inactive. T4 is slowly eliminated through its major metabolic pathway to T3 via sequential deiodination, where approximately 80% of circulating T3 is derived from peripheral T4. The liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. Elimination of T4 and T3 involves hepatic conjugation to glucuronic and sulfuric acids. The hormones undergo enterohepatic circulation as conjugates are hydrolyzed in the intestine and reabsorbed. Conjugated compounds that reach the colon are hydrolyzed and eliminated as free compounds in the feces. Other minor T4 metabolites have been identified.

Yields l-tyrosine in rabbit, in rat /From table/ Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. T-14

Yields 3,3',5-triiodo-L-thyronine in man, rat, dog, rabbit. /From table/ Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. T-14

Yields l-thyroxine-4'-beta-d-glucuronide in dog, in man, in rat. Yields l-thyroxine-4'-sulfate in dog. /From table/ Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. T-14

Yields 3,3',5,5'-tetraiodothyropyruvic acid in rat. Yields l-thyronine in rat. /From table/ Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. T-14

Yields 3,3'-diiodo-l-thyronine in dog. Yields 3,3',5,5'-tetraiodothyroacetic acid in man, in rat. /From table/ Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. T-14

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Biological Half-Life
T₄ half-life is 6 to 7 days. T₃ half-life is 1 to 2 days.

In dogs orally administered levothyroxine has relatively ... short elimination half life when compared to humans. ... The serum half life is approximately 12-16 hours. Plumb D.C. Veterinary Drug Handbook. 8th ed. (pocket). Ames, IA: Wiley-Blackwell, 2015., p. 842

The usual plasma half-lives of thyroxine and triiodothyronine are 6-7 days and approximately 1-2 days, respectively. The plasma half-lives of thyroxine and triiodothyronine are decreased in patients with hyperthyroidism and increased in those with hypothyroidism.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Levothyroxine (T4) is a normal component of human milk. Limited data on exogenous replacement doses of levothyroxine during breastfeeding indicate no adverse effects in infants. The American Thyroid Association recommends that subclinical and overt hypothyroidism should be treated with levothyroxine in lactating women seeking to breastfeed. Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating mothers with low milk supply. Levothyroxine dosage requirement may be increased in the postpartum period compared to prepregnancy requirements in patients with Hashimoto's thyroiditis.
◉ Effects in Breastfed Infants
Effects of exogenous thyroid hormone administration to mothers on their infant have not been reported. One case of apparent mitigation of cretinism in hypothyroid infants by breastfeeding has been reported, but the amounts of thyroid hormones in milk are not optimal, and this result has been disputed. The thyroid hormone content of human milk from the mothers of very preterm infants appears not to be sufficient to affect the infants' thyroid status. The amounts of thyroid hormones in milk are apparently not sufficient to interfere with diagnosis of hypothyroidism.
In a telephone follow-up study, 5 nursing mothers reported taking levothyroxine (dosage unspecified). The mothers reported no adverse reactions in their infants.
One mother who had undergone a thyroidectomy was taking levothyroxine 100 mcg daily as well as calcium carbonate and calcitriol. Her breastfed infant was reportedly "thriving" at 3 months of age.
A woman with propionic acidemia took levothyroxine 50 mcg daily as well as biotin, carnitine, and various amino acids while exclusively breastfeeding her infant for 2 months and nonexclusively for 10 months. At that time, the infant had normal growth and development.
◉ Effects on Lactation and Breastmilk
Adequate thyroid hormone serum levels are required for normal lactation. Replacing deficient thyroid levels should improve milk production caused by hypothyroidism. Supraphysiologic doses would not be expected to further improve lactation.

[1]. Association between genetic polymorphism and levothyroxine bioavailability in hypothyroid patients. Endocr J. 2018 Mar 28;65(3):317-323.

[2]. Levothyroxine treatment generates an abnormal uterine contractility patterns in an in vitro animalmodel. J Clin Transl Endocrinol. 2015 Sep 9;2(4):144-149.

Levothyroxine Sodium is the sodium salt of levothyroxine, a synthetic levoisomer of thyroxine (T4) that is similar to the endogenous hormone produced by the thyroid gland. In peripheral tissues, levothyroxine is deiodinated by 5'-deiodinase to form triiodothyronine (T3). T3 enters the cell and binds to nuclear thyroid hormone receptors; the activated hormone-receptor complex in turn triggers gene expression and produces proteins required in the regulation of cellular respiration; thermogenesis; cellular growth and differentiation; and the metabolism of proteins, carbohydrates and lipids. T3 also exhibits cardiostimulatory effects.
The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (MONOIODOTYROSINE) and the coupling of iodotyrosines (DIIODOTYROSINE) in the THYROGLOBULIN. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroxine is peripherally deiodinated to form TRIIODOTHYRONINE which exerts a broad spectrum of stimulatory effects on cell metabolism.

C15H10I4NNAO4

798.85

798.668

C, 22.55; H, 1.26; I, 63.54; N, 1.75; Na, 2.88; O, 8.01

55-03-8

L-Thyroxine;51-48-9;L-Thyroxine sodium salt pentahydrate;6106-07-6; Thyroxine sulfate;77074-49-8;L-Thyroxine sodium salt pentahydrate;6106-07-6;L-Thyroxine sodium;55-03-8;L-Thyroxine-13C6-1;1217780-14-7;Biotin-(L-Thyroxine);149734-00-9;Biotin-hexanamide-(L-Thyroxine);2278192-78-0;Thyroxine hydrochloride-13C6;1421769-38-1;L-Thyroxine-13C6;720710-30-5;L-Thyroxine-13C6,15N;1431868-11-9

23665037

Off-white to light yellow solid powder

576.3ºC at 760 mmHg

207-210 (dec.)(lit.)ºC

302.3ºC

3.601

141.76

7

10

5

30

426

1

C1=C(C=C(C(=C1I)OC2=CC(=C(C(=C2)I)O)I)I)C[C@@H](C(=O)[O-])N.O.O.O.O.O.[Na+]

JMHCCAYJTTWMCX-QWPJCUCISA-M

InChI=1S/C15H11I4NO4.Na.5H2O/c16-8-4-7(5-9(17)13(8)21)24-14-10(18)1-6(2-11(14)19)3-12(20)15(22)23;;;;;;/h1-2,4-5,12,21H,3,20H2,(H,22,23);;5*1H2/q;+1;;;;;/p-1/t12-;;;;;;/m0....../s1

sodium;(2S)-2-amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]propanoate;pentahydrate

Levothyroxine sodium; L-Thyroxine sodium; 55-03-8; Euthyrox; Unithroid; levothroid; Levoxyl; Novothyrox;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮和光照。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~62.5 mg/mL (~78.24 mM)
0.5 M NaOH : 25 mg/mL (~31.29 mM)
H2O : ~14 mg/mL (~17.53 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (2.60 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: 2.08 mg/mL (2.60 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
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10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
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