TS (Ki = 1.3 nM); DHFR (IC50 = 7.2 nM)

培美曲塞（LY231514）二钠是一种新型经典抗叶酸药物，其抗肿瘤活性可能来自于其多聚谷氨酸代谢物，可同时多重抑制多种重要的叶酸需求酶。目前已知存在的 FPGS 酶的最佳底物之一是培美曲塞 (LY231514)（K_m=1.6 μM 和 V_max/K_{m< /sub>=621）。 LY231514 的选择性和抗肿瘤活性可能很大程度上受到多谷氨酸化和这种新药的多谷氨酸代谢物的影响。 LY23l5l4 的五谷氨酸比 LY23l5l4 强 100 倍（Ki=3.4 nM），而 LY23l5l4 仅中度抑制 TS（Ki=340 nM，重组小鼠）[ 1]。这使得 LY231514 成为最有效的叶酸 TS 抑制剂之一。}

培美曲塞二钠在人 H460 非小细胞肺癌异种移植物中引起持续时间依赖性肿瘤生长延迟 (TGD)。

观察到产物 7,8-二氢叶酸的形成导致 340 nm 处吸光度增加，然后将其用于测量 TS 活性。测定缓冲液的成分如下：25 mM MgCl₂、6.5 mM 甲醛、1 mM EDTA、75 mM 2-巯基乙醇、50 mM N-三[羟甲基·甲基-2-氨基乙磺酸]。 hIS、6R-MTHF 和脱氧尿苷酸单磷酸的浓度分别为 30 μM、100 μM 和 30 nM（1.7 毫单位/mL）。在 6R-MTHF 浓度下测试未抑制的反应和六种抑制剂浓度。 K_{i app} 值是通过应用非线性回归分析并在 ENZFITTER 程序的帮助下将数据拟合到 Morrison 方程而获得的。 Ki 值的计算公式如下： 当 [S] 等于 30 μM，Km 等于 3 μM 时，K_{i app}= K_i(1 + [S ]/K_m）。 NADPH 和 7,8-二氢叶酸（底物）在 340 nm 处消失，这就是 DHFR 活性的分光光度分析的方法。该反应在 0.5 mL 50 mM 磷酸钾缓冲液中于 25°C 下进行。缓冲液的 pH 值为 7.5，含有 150 mM KCl、10 nM 2-巯基乙醇和 14 nM (0.34 milliunitlmL) DHFR。 7,8-二氢叶酸的浓度为 5、10 或 15 μM，而 NADPH 的浓度为 10 μM。测试了七种抑制剂浓度以及每个 7,8-二氢叶酸饱和度下的未抑制反应。 ENZFITI'ER 微机程序通过非线性回归分析将数据拟合到 Morrison 方程，从而确定 K_{i app} 值。对于每一种使用的 7,8-二氢叶酸，[S] 代表其浓度，K_m 相当于 0.15 μM。 K_{i app}= K_i(1 + [S]/K_m)。当 5,8-二脱氮杂叶酸在 295 nm 处形成时，会观察到吸光度增加，这就是 GARFT 活性的分光光度分析的定量方法。反应溶剂由 50% 甘油、25% HEPES 和 50% α-硫代甘油组成，pH 值为 7.5，25°C。使用以下浓度的底物和酶：10 μM α,β-甘氨酰胺核糖核苷酸、0-10 μM 10-甲酰基-5,8-二脱氮杂叶酸和 10 nM（1.9 毫单位/mL）GARFT。 Ki 值使用 Beckman DU640 分光光度计的酶机制程序确定，该程序使用非线性回归分析将数据拟合到用于竞争性抑制的 Michaelis-Menten 方程。

通过创建剂量反应曲线可以找到 50% 生长抑制 (IC50) 所需的浓度。培美曲塞二钠溶解于 DMSO 中，起始浓度为 4 mg/mL。然后用细胞培养基调节浓度。 124 孔簇板充满 2.0 mL 完全培养基中的 CCRF-CEM 白血病细胞。为了使 DMSO 最终体积达到 0.5%，重复孔中充满了不同浓度的培美曲塞二钠。在 5% CO₂ 空气气氛中，将板在 37°C 下孵育 72 小时。孵育结束时测量 ZBI Coulter 计数器上的细胞计数。在多项研究中，确定了每种化合物在 300 μM AICA、5 μM 胸苷、100 μM 次黄嘌呤或 5 μM 乙二苷和 100 μM 次黄嘌呤混合物中的半衰期。通过修改原始 MTT 比色测定法来测定贴壁肿瘤细胞的细胞毒性。在平底 96 孔组织培养板中，每孔使用 100 μL 测定培养基接种人类肿瘤细胞。测定培养基中叶酸的唯一来源是 2.3 μM 或 2 nM 叶酸，以及 10% FCS 和不含叶酸的 RPMI 1640。未填充孔 1A。抗叶酸储备溶液（每毫升 1 毫克）制备于Dulbecco's PBS，然后在 PBS 中连续进行 2 倍稀释。一式三份的孔中填充有每种浓度的 10 μL 等分试样。将板在空气中含有 5% CO2 的湿润气氛中于 37°C 孵育 72 小时。 MTT 以 5 mg/mL 的浓度溶解在 PBS 中后，将 10 µL MTF 库存溶液添加到测定的每个孔中。然后将板在 37°C 下再孵育两小时。孵育后每孔加入 100 μL DMSO。在甲臜完全溶解后，使用 570 nm 的测试波长和 630 nm 的参考波长在 Dynatech MR600 读数器上读取板。与未处理的对照相比，阻碍细胞生长 50% 所需的药物浓度称为抑制浓度 (IC50)。

Mice: The mice used are female CBA mice and female NOD/SCID mice (NOD.CB17-Prkdc^scid) that are 6–8 weeks old. In order to investigate the synergistic effect of premetrexed (100 mg/kg) in combination with anti-CD25 Ab or IgG control, tumor-bearing mice receive it intraperitoneally (i.p.) from days 4–8 (5 consecutive days). Based on earlier research conducted on mice, the current study's Pemetrexed dosage and schedule were chosen.

Absorption, Distribution and Excretion
The pharmacokinetics of pemetrexed when pemetrexed was administered as a single agent in doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally with the increase in dose. The pharmacokinetics of pemetrexed did not change over multiple treatment cycles.
Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. In vitro studies indicated that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that is involved in the active secretion of pemetrexed.
Pemetrexed has a steady-state volume of distribution of 16.1 liters.
The total systemic clearance of pemetrexed is 91.8 mL/min in patients with normal renal function (creatinine clearance of 90 mL/min). As renal function decreases, the clearance of pemetrexed decreases, and exposure (AUC) of pemetrexed increases.
Pemetrexed ... is primarily eliminated in the urine ... within the first 24 hours following administration.
The total systemic clearance of pemetrexed is 91.8 mL per min in patients with normal renal function (creatinine clearance of 90 mL per min). The clearance decreases, and exposure (AUC) increases, as renal function decreases. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increase proportionally with dose.
The pharmacokinetics of pemetrexed administered as a single agent in doses ranging from 0.2 to 838 mg/sq m infused over a 10 minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed AUC and Cmax increase proportionally with dose. The pharmacokinetics of pemetrexed do not change over multiple treatment cycles. Pemetrexed has a steady-state volume of distribution of 16.1 L. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.
Time to ANC nadir with pemetrexed systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 38.3 to 316.8 ug per hr per mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures.
For more Absorption, Distribution and Excretion (Complete) data for PEMETREXED (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Pemetrexed is not metabolized to an appreciable extent by the liver.
Pemetrexed is not metabolised to an appreciable extent and ... 70% to 90% of the dose recovered unchanged ...

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Biological Half-Life
The elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min).
... The elimination half life of pemetrexed is 3.5 hours in patients with normal renal function (Ccr90 mL/min).

Hepatotoxicity
Pemetrexed therapy is associated with a low-to-moderate rate of serum enzyme elevations, but these are generally mild, transient and without accompanying symptoms or jaundice. Serum ALT or AST elevations above 5 times ULN occur in 1% to 6% of patients, but are usually self-limited in course and rarely require dose modification or discontinuation. No instances of clinically apparent acute liver injury attributed to pemetrexed have been reported. In addition, pemetrexed has not been linked to sinusoidal obstruction syndrome or to reactivation of hepatitis B, but it is rarely used in high doses in neoplastic disease or in conditioning regimens for bone marrow transplantation, situations in which other neoplastic agents are commonly associated with these complications.
Likelihood score: E* (unlikely but suspected cause of liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Most sources consider breastfeeding to be contraindicated during maternal high-dose antineoplastic drug therapy. The manufacturer recommends that mothers should not to breastfeed during treatment with pemetrexed and for one week after the last dose. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk.[1] Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.[2]
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
28170295

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Protein Binding
In vitro studies indicated that pemetrexed is 81% bound to plasma proteins.

[1]. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 1997 Mar 15;57(6):1116-23.

[2]. Synergistic antitumor effects of regulatory T cell blockade combined with pemetrexed in murine malignantmesothelioma. J Immunol. 2010 Jul 15;185(2):956-66.

Pemetrexed is an N-acylglutamic acid in which the N-acyl group is specified as 4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl. Inhibits thymidylate synthase (TS), 421 dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). It has a role as an antineoplastic agent, an antimetabolite, an EC 2.1.1.45 (thymidylate synthase) inhibitor, an EC 1.5.1.3 (dihydrofolate reductase) inhibitor and an EC 2.1.2.2 (phosphoribosylglycinamide formyltransferase) inhibitor. It is a pyrrolopyrimidine and a N-acyl-L-glutamic acid. It is a conjugate acid of a pemetrexed(2-).
Pemetrexed is a chemotherapy drug that is manufactured and marketed by Eli Lilly and Company under the brand name Alimta. It is indicated for use in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is either unresectable or who are otherwise not candidates for curative surgery. Its use in non-small cell lung cancer has also been investigated. Pemetrexed was first approved by the FDA in February 4, 2004.
Pemetrexed is a Folate Analog Metabolic Inhibitor. The mechanism of action of pemetrexed is as a Folic Acid Metabolism Inhibitor.
Pemetrexed is a parenterally administered folate antagonist and antineoplastic agent, used in the treatment of non-small cell lung cancer and malignant mesothelioma. Pemetrexed therapy has been associated with moderate rates of serum enzyme elevations during therapy, but has not been convincingly linked to instances of acute, clinically apparent liver injury.
Pemetrexed is a synthetic pyrimidine-based antifolate. Pemetrexed binds to and inhibits the enzyme thymidylate synthase (TS), which catalyses the methylation of 2'-deoxyuridine-5'-monophosphate (dUMP) to 2'-deoxythymidine-5'-monophosphate (dTMP), an essential precursor in DNA synthesis.
A guanine-derived ANTINEOPLASTIC AGENT that functions as a NUCLEIC ACID SYNTHESIS INHIBITOR through its binding to, and inhibition of, THYMIDYLATE SYNTHASE.
See also: Pemetrexed Disodium (active moiety of); Pemetrexed disodium heptahydrate (active moiety of); Pemetrexed Disodium Hemipentahydrate (active moiety of) ... View More ...

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Drug Indication
Pemetrexed is indicated for the treatment of the following conditions: **Non-squamous non-small cell lung cancer (NSCLC)** - in combination with [pembrolizumab] and platinum-based chemotherapy as initial treatment in metastatic disease where no EGFR or ALK genomic tumour aberrations exist - in combination with [cisplatin] as initial treatment for locally advanced or metastatic disease - as maintenance treatment for locally advanced or metastatic disease that has not progressed following four cycles of platinum-based chemotherapy - recurrent metastatic disease following prior chemotherapy - as monotherapy for the second-line treatment of patients with locally advanced or metastatic non-squamous non-small cell lung cancer **Malignant pleural mesothelioma** - in combination with [cisplatin] for the initial treatment of patients with malignant pleural mesothelioma. In the US, it is reserved for patients whose disease is unresectable or otherwise not candidates for curative surgery.
FDA Label
Malignant pleural mesotheliomaPemetrexed Accord in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma. Non-small cell lung cancer Pemetrexed Accord in combination with cisplatin is indicated for the first line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. Pemetrexed Accord is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. Pemetrexed Accord is indicated as monotherapy for the second line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology.
Malignant pleural mesotheliomaPemetrexed in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma. Non-small cell lung cancer Pemetrexed in combination with cisplatin is indicated for the first line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. Pemetrexed is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. Pemetrexed is indicated as monotherapy for the second line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology.
Malignant pleural mesotheliomaPemetrexed Krka in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma. Non-small cell lung cancer Pemetrexed Krka in combination with cisplatin is indicated for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. Pemetrexed Krka is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. Pemetrexed Krka is indicated as monotherapy for the second-line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology.
Malignant pleural mesotheliomaPemetrexed Baxter in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma. Non-small cell lung cancer Pemetrexed Baxter in combination with cisplatin is indicated for the first line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology (see section 5. 1). Pemetrexed Baxter is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy (see section 5. 1). Pemetrexed Baxter is indicated as monotherapy for the second line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology (see section 5. 1).
Malignant pleural mesotheliomaPemetrexed Pfizer in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma. Non-small cell lung cancer Pemetrexed Pfizer in combination with cisplatin is indicated for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. Pemetrexed Pfizer is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. Pemetrexed Pfizer is indicated as monotherapy for the second-line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology.
Malignant pleural mesothelioma, , Ciambra in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma. , , Non-small cell lung cancer , , Ciambra in combination with cisplatin is indicated for the first line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. , , Ciambra is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. , , Ciambra is indicated as monotherapy for the second line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. ,
Malignant pleural mesothelioma Pemetrexed medac in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma. , , Non-small cell lung cancer Pemetrexed medac in combination with cisplatin is indicated for the first line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. , , Pemetrexed medac is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. , , Pemetrexed medac is indicated as monotherapy for the second line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. ,
Malignant pleural mesothelioma, , Pemetrexed Sandoz in combination with cisplatin is indicated for the treatment of chemotherapy naive patients with unresectable malignant pleural mesothelioma. , , Non-small cell lung cancer , , Pemetrexed Sandoz in combination with cisplatin is indicated for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. , , Pemetrexed Sandoz is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. , , Pemetrexed Sandoz is indicated as monotherapy for the second-line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. ,
Malignant pleural mesotheliomaPemetrexed Fresenius Kabi in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma. Non-small cell lung cancer Pemetrexed Fresenius Kabi in combination with cisplatin is indicated for the first line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. Pemetrexed Fresenius Kabi is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. Pemetrexed Fresenius Kabi is indicated as monotherapy for the second line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology.
Malignant pleural mesotheliomaAlimta in combination with cisplatin is indicated for the treatment of chemotherapy-naïve patients with unresectable malignant pleural mesothelioma. Non-small-cell lung cancer Alimta in combination with cisplatin is indicated for the first-line treatment of patients with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology. Alimta is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. Alimta is indicated as monotherapy for the second line treatment of patients with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology.
Malignant pleural mesotheliomaPemetrexed Lilly in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma. Non-small cell lung cancer Pemetrexed Lilly in combination with cisplatin is indicated for the first line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. Pemetrexed Lilly is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. Pemetrexed Lilly is indicated as monotherapy for the second line treatment of patients with locally advanced or metastatic non small cell lung cancer other than predominantly squamous cell histology.
Malignant pleural mesotheliomaPemetrexed Hospira UK Limited in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma. Non-small cell lung cancer Pemetrexed Hospira UK Limited in combination with cisplatin is indicated for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology (see SmPC section 5. 1). Pemetrexed Hospira UK Limited is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy (see SmPC section 5. 1). Pemetrexed Hospira UK Limited is indicated as monotherapy for the second-line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology (see SmPC section 5. 1).

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Mechanism of Action
Pemetrexed is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), all folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.
Pemetrexed is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), all folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folyl polyglutamate synthase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.
... Activity of the /pemetrexed/ may be partially preserved under conditions in which cells are highly resistant to other thymidylate synthase inhibitors, possibly because of premetrexed's secondary inhibitory effects on purine synthesis. ... Pemetrexed activity is modulated by natural folates within cells that compete for polyglutamation at the level of folylpolyglutamate synthetase. Cells resistant to methotrexate because of impaired transport via the reduced folate carrier may retain partial sensitivity to pemetrexed. This is due to concurrent diminished transport of physiologic reduced folates and contraction of the cellular folate pool, thereby relaxing the usual level of suppression of pemetrexed polyglutamation. The risk of pemetrexed toxicity is increased when cellular folates are suboptimal.

C20H21N5O6

427.41

427.149

C, 56.20; H, 4.95; N, 16.39; O, 22.46

137281-23-3

Pemetrexed disodium;150399-23-8;Pemetrexed disodium heptahydrate;357166-29-1;Pemetrexed disodium hemipenta hydrate;357166-30-4;Pemetrexed-d5;1129408-57-6

135410875

White to off-white solid powder

1.6±0.1 g/cm3

1.724

-0.03

191.26

6

7

9

31

748

1

O=C1C2=C(N=C(N([H])[H])N1[H])N([H])C([H])=C2C([H])([H])C([H])([H])C1C([H])=C([H])C(C(N([H])[C@]([H])(C(=O)O[H])C([H])([H])C([H])([H])C(=O)O[H])=O)=C([H])C=1[H]

WBXPDJSOTKVWSJ-ZDUSSCGKSA-N

InChI=1S/C20H21N5O6/c21-20-24-16-15(18(29)25-20)12(9-22-16)6-3-10-1-4-11(5-2-10)17(28)23-13(19(30)31)7-8-14(26)27/h1-2,4-5,9,13H,3,6-8H2,(H,23,28)(H,26,27)(H,30,31)(H4,21,22,24,25,29)/t13-/m0/s1

(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioic acid

Pemetrexed; HSDB 7316; HSDB7316; HSD-7316; Alimta

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: ~250 mg/mL (~584.9 mM)
H2O: < 0.1 mg/mL

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.87 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 (4.87 mM) (饱和度未知) 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), 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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配方 3 中的溶解度: ≥ 2.08 mg/mL (4.87 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (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 储备液加入到 900 μL 玉米油中并混合均匀。

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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：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。