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

Pemetrexed (LY231514) disodium is a novel classical antifolate, and its antitumor activity may come from its polyglutamated metabolites, which may simultaneously and multiplely inhibit several important folate-requiring enzymes. One of the best substrates for the enzyme FPGS that is currently known to exist is pemetrexed (LY231514) (K_m=1.6 μM and V_max/K_m=621). The selectivity and antitumor activity of LY231514 are probably greatly influenced by polyglutamation and the polyglutamated metabolites of this novel agent. The pentaglutamate of LY23l5l4 is 100-fold more potent (K_i=3.4 nM) than LY23l5l4, which only moderately inhibits TS (K_i=340 nM, recombinant mouse)[1]. This makes LY231514 one of the most potent folate-based TS inhibitors.

Pemetrexed disodium causes a duration-dependent tumor growth delay (TGD) in the human H460 non-small cell lung carcinoma xenograft.

The formation of the product, 7,8-dihydrofolate, was observed to result in an increase in absorbance at 340 nm, which was then used to measure TS activity. The assay buffer has the following contents: 25 mM MgC1₂, 6.5 mM formaldehyde, 1 mM EDTA, 75 mM 2-mercaptoethanol, 50 mM N-tris[hydroxymethyljmethyl-2-aminoethanesulfonic acid]. The concentrations of hIS, 6R-MTHF, and deoxyuridylate monophosphate are 30 μM, 100 μM, and 30 nM (1.7 milliunits/mL), respectively. An uninhibited reaction and six inhibitor concentrations are tested at the 6R-MTHF concentration. K_{i app} values are obtained by applying nonlinear regression analysis, with the assistance of the ENZFITTER program, to fit the data to the Morrison equation. The following equation is used to calculate Ki values: With [S] equal to 30 μM and Km equal to 3 μM, K_{i app}= K_i(1 + [S]/K_m). NADPH and 7,8-dihydrofolate, the substrates, disappear at 340 nm, which is how spectrophotometric analysis of DHFR activity is done. The reaction occurs in 0.5 mL of 50 mM potassium phosphate buffer at 25°C. The buffer has a pH of 7.5, 150 mM KC1, 10 nM 2-mercaptoethanol, and 14 nM (0.34 milliunitlmL) DHFR. 7,8-dihydrofolate is varied at 5, 10, or 15 μM, while NADPH is present at a concentration of 10 μM. Seven inhibitor concentrations are tested along with an uninhibited reaction at each 7,8-dihydrofolate saturation. Fitting the data to the Morrison equation through nonlinear regression analysis is how the ENZFITI'ER microcomputer program determines the K_{i app} values. For every 7,8-dihydrofolate used, [S] represents its concentration, and K_m is equivalent to 0.15 μM. K_{i app}= K_i(1 + [S]/K_m). When 5,8-dideazafolate is formed at 295 nm, an increase in absorbance is observed, which is how spectrophotometric analysis of GARFT activity is quantified. 50% glycerol, 25% HEPES, and 50% a-thioglycerol at a pH of 7.5 at 25°C make up the reaction solvent. Substrates and enzyme were used at the following concentrations: 10 μM α,β-glycinamide ribonucleotide, 0–10 μM 10-formyl–5,8–dideazafolic acid, and 10 nM (1.9 milliunits/mL) GARFT. Ki values are determined using the Beckman DU640 spectrophotometer's Enzyme Mechanism program, which fits data to the Michaelis-Menten equation for competitive inhibition using nonlinear regression analysis.

The concentration necessary for 50% inhibition of growth (IC50) is found by creating dose-response curves. At a starting concentration of 4 mg/mL in DMSO, pemetrexed disodium is dissolved. The concentration is then adjusted with cell culture medium. One hundred twenty-four well Cluster plates are filled with 2.0 mL of CCRF-CEM leukemia cells in complete medium. To make DMSO final volume of 0.5%, replicate wells are filled with pemetrexed disodium at different concentrations. In a 5% CO₂ in air atmosphere, the plates are incubated for 72 hours at 37°C. Cell counts on a ZBI Coulter counter are measured at the conclusion of the incubation. In multiple investigations, the half-life of each compound is ascertained when subjected to 300 μM AICA, 5 μM thymidine, 100 μM hypoxanthine, or a mix of 5 μM hymidine and 100 μM hypoxanthine. Cell cytotoxicity for adherent tumor cells is determined by modifying the original MTT colorimetric assay. In 96-well tissue culture plates with a flat bottom, 100 μL of assay medium is used to seed human tumor cells per well. The only sources of folate in the assay medium are 2.3 μM or 2 nM folic acid, along with 10% FCS and folic acid-free RPMI 1640. Well 1A is not filled in. Antifolate stock solutions (one milligram per milliliter) are prepared in Dulbecco's PBS, and then successive 2-fold dilutions are made in PBS. Triplicate wells are filled with ten-μL aliquots of each concentration. Plates are incubated at 37 °C for 72 hours in an atmosphere that is humidified with 5% CO2 in the air. 10 μL of stock MTF solution is added to each well of an assay after MTT has been dissolved in PBS at a concentration of 5 mg/mL. The plates are then incubated for an additional two hours at 37 °C. 100 μL of DMSO is added to each well after incubation. The plates are read on a Dynatech MR600 reader using a test wavelength of 570 nm and a reference wavelength of 630 nm following complete formazan solubilization. The drug concentration needed to impede cell growth by 50% in comparison to untreated controls is known as the inhibitory concentration (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

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

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)