托吡酯 | 97240-79-4

• 物质功能分类: 原料药 - 神经系统用药 - 抗癫痫及抗惊厥药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氧吡喃
• 中文名称: 托吡酯
• 中文别名: 2,3:4,5-双-0-(1-甲基亚乙基)-Β-吡喃果糖氨基磺酸酯；托佩马特；妥吡酯；妥泰,2,3:4,5-双-0-(1-甲基亚乙基)-β-吡喃果糖氨基磺酸酯；2,3,4,5-双-o-(1-甲基亚乙基)-β-d-吡喃果糖氨基磺酸酯；2,3,4,5-双-O-(1-甲基亚乙基)-Β-D-吡喃果糖氨基磺酸酯；妥泰
• 英文名称: topiramate
• 英文别名: TPM；2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate；Topamax；[(1R,2S,6S,9R)-4,4,11,11-tetramethyl-3,5,7,10,12-pentaoxatricyclo[7.3.0.02,6]dodecan-6-yl]methyl sulfamate
• CAS: 97240-79-4
• 化学式: C₁₂H₂₁NO₈S
• mdl: MFCD00865320
• 分子量: 339.367
• InChiKey: KJADKKWYZYXHBB-XBWDGYHZSA-N

物化性质

• 熔点：
  125°C
• 比旋光度：
  D23 -34.0° (c = 0.4 in methanol)
• 沸点：
  438.7±55.0 °C(Predicted)
• 密度：
  1.336±0.06 g/cm3(Predicted)
• 闪点：
  9℃
• 溶解度：
  二甲基亚砜：44 mg/mL
• LogP：
  2.970 (est)
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from ethyl acetate and benzene
• 味道：
  Bitter
• 蒸汽压力：
  7.0X10-8 mm Hg at 25 °C (est)
• 水溶性：
  -1.7
• 旋光度：
  Specific optical rotation = -34 deg/D (c = 0.4 in methanol)
• 碰撞截面：
  170.1 Ų [M+Na]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  124
• 氢给体数：
  1
• 氢受体数：
  9

ADMET

代谢

托吡酯的代谢物不被认为具有活性。托吡酯的代谢特点包括葡萄糖醛酸化、羟基化和水解反应，这些反应导致产生六个次要代谢物。托吡酯的一些代谢物包括2,3-去异丙叉基托吡酯、4,5-去异丙叉基托吡酯、9-羟基托吡酯和10-羟基托吡酯。

The metabolites of topiramate are not known to be active. The metabolism of topiramate is characterized by reactions of glucuronidation, hydroxylation and hydrolysis that lead to the production of six minor metabolites. Some of topiramate's metabolites include 2,3-desisopropylidene topiramate, 4,5-desisopropylidene topiramate, 9-hydroxy topiramate, and 10-hydroxy topiramate.

来源:DrugBank

代谢

托吡酯在人体内不是广泛代谢的。已经确定了六种次要代谢物（通过羟基化、水解和葡萄糖醛酸化形成），其中没有一个构成超过给药剂量5%的部分。

Topiramate is not extensively metabolized. Six minor metabolites (formed by hydroxylation, hydrolysis, and glucuronidation) have been identified in humans, with none constituting more than 5% of an administered dose.

来源:Hazardous Substances Data Bank (HSDB)

代谢

2,3:4,5-双-O-(1-甲基乙基亚胺)-β-D-果糖磺酰胺（托吡酯，Topamax，TPM）的代谢和排泄在动物和人类中进行了研究。放射性标记的[14C] TPM通过口服给药给小鼠、大鼠、家兔、狗和人类。收集并分析了血浆、尿液和粪便样本。在这些样本中分离并鉴定了TPM及其总共12种代谢物。代谢物的形成包括TPM的7-或8-甲基上的异丙基亚胺的羟基化并随后重排，另一个异丙基亚胺的10-甲基上的羟基化，2,3-O-异丙基亚胺的水解，4,5-O-异丙基亚胺的水解，磺酰胺基团的裂解，葡萄糖醛酸结合和硫酸结合。在动物和人类的尿液中回收了大量未改变的TPM。在小鼠、雄性大鼠、家兔和狗中，TPM的主要代谢物似乎是通过2,3-O-异丙基亚胺基团的水解形成的。

The metabolism and excretion of 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate (TOPAMAX, topiramate, TPM) have been investigated in animals and humans. Radiolabeled [14C] TPM was orally administered to mice, rats, rabbits, dogs and humans. Plasma, urine and fecal samples were collected and analyzed. TPM and a total of 12 metabolites were isolated and identified in these samples. Metabolites were formed by hydroxylation at the 7- or 8-methyl of an isopropylidene of TPM followed by rearrangement, hydroxylation at the 10-methyl of the other isopropylidene, hydrolysis at the 2,3-O-isopropylidene, hydrolysis at the 4,5-O-isopropylidene, cleavage at the sulfamate group, glucuronide conjugation and sulfate conjugation. A large percentage of unchanged TPM was recovered in animal and human urine. The most dominant metabolite of TPM in mice, male rats, rabbits and dogs appeared to be formed by the hydrolysis of the 2,3-O-isopropylidene group.

来源:Hazardous Substances Data Bank (HSDB)

代谢

未广泛代谢，70%的剂量以原形在尿液中排出。另外30%通过肝脏代谢成六种代谢物（通过羟基化、水解和葡萄糖醛酸化形成），其中任何一种都不超过给药剂量的5%。有证据表明托吡酯存在肾小管重吸收。 消除途径：托吡酯未广泛代谢，主要以其原形通过尿液排出（约占总给药剂量的70%）。 半衰期：19至23小时。重复给药后，缓释制剂的平均消除半衰期为31小时。

Not extensively metabolized, 70% of the dose is eliminated unchanged in the urine. The other 30% is metabolized hepatically to six metabolites (formed by hydroxylation, hydrolysis, and glucuronidation), none of which constitute more than 5% of an administered dose. There is evidence of renal tubular reabsorption of topiramate. Route of Elimination: Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Half Life: 19 to 23 hours. The mean elimination half-life was 31 hours following repeat administration of the extended-release formulation.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

托吡酯的确切作用机制尚不清楚。然而，研究表明托吡酯以时间依赖性的方式阻断由神经元的持续去极化引发的重复动作电位，这表明了一种状态依赖性的钠通道阻断作用。托吡酯还能增强某些亚型的γ-氨基丁酸（GABA）神经递质在GABA_A受体（控制一个完整的氯离子通道）上的活性，表明可能通过增强GABA的活性来实现作用机制。托吡酯还展示了对抗AMPA/海人藻酸亚型的谷氨酸兴奋性氨基酸受体的作用。它还抑制碳酸酐酶（特别是同工酶II和IV），但这种作用较弱，不太可能与它的抗惊厥作用相关。

The precise mechanism of action of topiramate is not known. However, studies have shown that topiramate blocks the action potentials elicited repetitively by a sustained depolarization of the neurons in a time-dependent manner, suggesting a state-dependent sodium channel blocking action. Topiramate also augments the activity of the neurotransmitter gamma-aminobutyrate (GABA) at some subtypes of the GABA_A receptor (controls an integral chloride channel), indicating a possible mechanism through potentiation of the activity of GABA. Topiramate also demonstrates antagonism of the AMPA/kainate subtype of the glutamate excitatory amino acid receptor. It also inhibits carbonic anhydrase (particularly isozymes II and IV), but this action is weak and unlikely to be related to its anticonvulsant actions.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

前瞻性研究表明，长期使用托吡酯治疗的患者中，不到1%的人血清转氨酶水平会升高。临床上明显的托吡酯肝毒性相当罕见，通常发生在接受多种其他抗惊厥药物的患者中。托吡酯通过CYP 3A4代谢，可能会增加丙戊酸或其他抗惊厥药物肝毒性的风险。一种独特的综合征是在长期丙戊酸治疗中添加（或增加剂量）托吡酯后2到3周内出现乏力、虚弱、血清转氨酶显著升高和血氨升高。虽然丙戊酸单独可以引起类似的综合征，但与单独使用丙戊酸相比，联合使用时似乎更常见（约1%），而单独使用丙戊酸时约为0.1%。这种综合征具有雷耶综合症的特征（高氨血症、低血糖、快速逆转损伤），在许多情况下，它是由急性病毒性疾病引起的。托吡酯本身很少与临床上明显的肝损伤有关，损伤的临床特征和过程尚未明确。托吡酯尚未与抗惊厥药物超敏反应综合症病例有关联，被认为是该综合症患者的安全替代品。

Prospective studies suggest that less than 1% of subjects develop elevations in serum aminotransferase levels during long term topiramate therapy. Clinically apparent hepatotoxicity from topiramate is quite rare and usually arises in patients receiving multiple other anticonvulsants. Topiramate is metabolized by CYP 3A4 and may increase the risk of valproate or other anticonvulsant hepatotoxicity. A distinctive syndrome is the development of lethargy, weakness with marked serum aminotransferase elevations and hyperammonemia arising within 2 to 3 weeks of the addition (or dose increase) of topiramate to long term valproate therapy. While valproate alone can cause a similar syndrome, it appears much more common (~1%) with the combination than with valproate alone (~0.1%). This syndrome has several features suggestive of Reye syndrome (hyperammonemia, hypoglycemia, rapid reversal of injury) and in many instances is preceded by a acute viral illness. Topiramate by itself has only rarely been linked to clinically apparent liver injury and the clinical features and course of injury have not been well defined. Topiramate has not been linked to cases of the anticonvulsant hypersensitivity syndrome and is considered a safe alternative in patients with that syndrome.

来源:LiverTox

毒理性

• 药物性肝损伤

托吡酯

Compound:topiramate

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

在400毫克剂量的临床试验中，托吡酯在1.8-4.3小时内达到最大浓度，范围在1.73-28.7微克/毫升。食物虽然会延迟达到峰值浓度的时间，但并未显著影响吸收程度。在肌酐清除率正常的患者中，稳态浓度在4天内达到。与托吡酯溶液相比，片剂形式的托吡酯的生物利用度约为80%。

After a 400mg dose in one clinical trial, topiramate reached maximal concentrations within 1.8-4.3 hours and ranged from 1.73-28.7 ug/mL. Food did not significantly affect the extent of absorption, despite delaying time to peak concentration. In patients with normal creatinine clearance, steady state concentrations are reached within 4 days. The bioavailability of topiramate in tablet form is about 80% compared to a topiramate solution.

来源:DrugBank

吸收、分配和排泄

• 消除途径

托吡酯主要通过肾脏消除。大约70-80%的消除剂量在尿液中以原形存在。

Topiramate is mainly eliminated through the kidneys. About 70-80% of the eliminated dose is found unchanged in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

托吡酯的平均表观分布容积在给予100mg至1200mg剂量时，范围从0.6-0.8 L/kg。托吡酯容易穿过血脑屏障。

The mean apparent volume of distribution of topiramate ranges from 0.6-0.8 L/kg when doses of 100mg to 1200mg are given. Topiramate readily crosses the blood-brain barrier.

来源:DrugBank

吸收、分配和排泄

• 清除

根据一项药代动力学研究，托吡酯的平均口服血浆清除率范围在22-36 mL/min，而肾清除率为17-18 mL/min。美国食品药品监督管理局（FDA）对托吡酯的标签说明，成年人的类似口服血浆清除率大约为20至30 mL/min。

The mean oral plasma clearance of topiramate ranges from 22-36 mL/min while the renal clearance is 17-18 mL/min, according to one pharmacokinetic study. The FDA label for topiramate indicates a similar oral plasma clearance of approximately 20 to 30 mL/min in adults.

来源:DrugBank

吸收、分配和排泄

托吡酯的吸收是快速的。片剂剂型的生物利用度约为80%，与溶液相比。食物不会影响托吡酯的生物利用度。

Absorption /of topiramate is/ rapid. The bioavailability of the tablet dosage form is about 80% as compared with that from a solution. Food does not effect the bioavailability of topiramate.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S26,S36
• 危险类别码：
  R36/37/38
• WGK Germany：
  3
• 海关编码：
  29350090
• 危险品运输编号：
  UN1230 - class 3 - PG 2 - Methanol, solution
• RTECS号：
  LS7083000
• 危险标志：
  GHS07
• 危险性描述：
  H315,H319,H335
• 危险性防范说明：
  P261,P305 + P351 + P338
• 储存条件：
  存放在0至10℃的环境中；请避免加热。

SDS

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SECTION 1: Identification of the substance/mixture and of the company/undertaking
Product identifiers
Product name : Topiramate
REACH No. : A registration number is not available for this substance as the substance
or its uses are exempted from registration, the annual tonnage does not
require a registration or the registration is envisaged for a later
registration deadline.
CAS-No. : 97240-79-4
Relevant identified uses of the substance or mixture and uses advised against
Identified uses : Laboratory chemicals, Manufacture of substances

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SECTION 2: Hazards identification
Classification of the substance or mixture
Classification according to Regulation (EC) No 1272/2008
Skin irritation (Category 2), H315
Eye irritation (Category 2), H319
Specific target organ toxicit