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
This study evaluated the pharmacokinetics of pemetrexed as monotherapy in 426 patients with various solid tumors, administered intravenously over 10 minutes at doses ranging from 0.2 to 838 mg/m². The total systemic exposure (AUC) and maximum plasma concentration (Cmax) of pemetrexed increased proportionally with increasing dose. The pharmacokinetics of pemetrexed remained unchanged across multiple treatment cycles. Pemetrexed is primarily excreted in the urine, with 70% to 90% of the dose excreted unchanged within 24 hours after administration. In vitro studies have shown that pemetrexed is a substrate of organic anion transporter 3 (OAT3), which is involved in the active secretion of pemetrexed. The steady-state volume of distribution of pemetrexed is 16.1 L. The total clearance of pemetrexed in patients with normal renal function (creatinine clearance of 90 mL/min) was 91.8 mL/min. With declining renal function, pemetrexed clearance decreases and exposure (AUC) increases. Pemetrexed is primarily excreted in the urine within 24 hours after administration. In patients with normal renal function (creatinine clearance of 90 mL/min), the total clearance of pemetrexed was 91.8 mL/min. With declining renal function, clearance decreases and exposure (AUC) increases. The total systemic exposure (AUC) and maximum plasma concentration (Cmax) of pemetrexed increase in a dose-dependent manner. The pharmacokinetics of pemetrexed monotherapy (dose range 0.2 to 838 mg/m², intravenous infusion over 10 minutes) were evaluated in 426 cancer patients with various solid tumors. The AUC and Cmax of pemetrexed increased in a dose-dependent manner. The pharmacokinetics of pemetrexed remained constant across multiple treatment cycles. The steady-state volume of distribution of pemetrexed is 16.1 L. In vitro studies have shown that pemetrexed binds to plasma proteins at a rate of approximately 81%. The degree of renal impairment does not affect its binding. The time to reach the lowest absolute neutrophil count (ANC) with systemic exposure (AUC) of pemetrexed within the exposure range of 38.3 to 316.8 μg/h/mL varied from 8 to 9.6 days within the same exposure range. The time to ANC recovery to baseline levels ranged from 4.2 to 7.5 days after the lowest point within the same exposure range. For more complete data on absorption, distribution, and excretion of pemetrexed (7 items), please visit the HSDB record page. Metabolism/Metabolites Pemetrexed is poorly metabolized in the liver. Pemetrexed is poorly metabolized, with 70% to 90% of the dose recovered unchanged… Biological Half-Life In patients with normal renal function (creatinine clearance 90 mL/min), the elimination half-life of pemetrexed is 3.5 hours. ...In patients with normal renal function (creatinine clearance 90 mL/min), the elimination half-life of pemetrexed is 3.5 hours.

Hepatotoxicity
Pemetrexed treatment is associated with low to moderate elevations in serum enzymes, but these elevations are usually mild, transient, and without accompanying symptoms or jaundice. 1% to 6% of patients may experience serum ALT or AST elevations exceeding 5 times the upper limit of normal, but these usually resolve spontaneously and rarely require dose adjustment or discontinuation. There are no reported cases of clinically significant acute liver injury caused by pemetrexed. Furthermore, pemetrexed has not been reported to be associated with hepatic sinusoidal obstruction syndrome or hepatitis B virus reactivation, but it is rarely used in pre-treatment regimens for neoplastic diseases or bone marrow transplantation, where other anti-tumor drugs are often associated with these complications. Probability score: E (Unlikely, but suspected cause of liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Most sources suggest that mothers receiving high-dose anti-tumor drug treatment should avoid breastfeeding. The manufacturer recommends that mothers should not breastfeed during pemetrexed treatment and for one week after the last dose. Chemotherapy may adversely affect the normal microbiota and chemical composition of breast milk. [1] Women who receive chemotherapy during pregnancy are more likely to experience breastfeeding difficulties. [2] ◉ Effects on breastfed infants ◉ No published information found as of the revision date. ◉ Effects on lactation and breast milk ◉ No published information found as of the revision date. 28170295

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Protein binding
In vitro studies have shown that pemetrexed binds to plasma proteins at a rate of 81%.

[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-acylglutamate compound with an N-acyl group of 4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl. It inhibits thymidine synthase (TS), dihydrofolate reductase (DHFR), and glycine nucleotide formyltransferase (GARFT). It possesses various pharmacological activities, including antitumor activity, antimetabolite activity, and inhibition of EC 2.1.1.45 (thymidine synthase), EC 1.5.1.3 (dihydrofolate reductase), and EC 2.1.2.2 (phospribosylglycine formyltransferase). It is a pyrrolopyrimidine compound and also an N-acyl-L-glutamate compound. It is the conjugate acid of pemetrexed (2-). Pemetrexed is a chemotherapy drug manufactured and marketed by Eli Lilly and Company under the brand name Alimta. It is used in combination with cisplatin to treat patients with malignant pleural mesothelioma who are unresectable or unsuitable for radical surgery. Its use in non-small cell lung cancer has also been studied. Pemetrexed was first approved by the U.S. Food and Drug Administration (FDA) on February 4, 2004. Pemetrexed is a folic acid analogue metabolism inhibitor. Its mechanism of action is as a folic acid metabolism inhibitor. Pemetrexed is a parenteral folic acid antagonist and antitumor drug used to treat non-small cell lung cancer and malignant mesothelioma. Elevated serum enzymes during pemetrexed treatment occur at a moderate rate, but there is no conclusive evidence that it is associated with cases of acute, clinically significant liver injury. Pemetrexed is a synthetic pyrimidine antifolate drug. Pemetrexed binds to and inhibits thymidine synthase (TS), an enzyme that catalyzes the methylation of 2'-deoxyuridine-5'-monophosphate (dUMP) to 2'-deoxythymidine-5'-monophosphate (dTMP), a crucial precursor in DNA synthesis. Pemetrexed is a guanine-derived antitumor drug that acts as a nucleic acid synthesis inhibitor by binding to and inhibiting thymidine synthase activity. See also: Pemetrexed disodium (active ingredient); Pemetrexed disodium heptahydrate (active ingredient). Pemetrexed disodium hemipentahydrate (active ingredient)...See more...

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Drug Indications
Pemetrexed is indicated for the treatment of the following diseases: Non-squamous non-small cell lung cancer (NSCLC) - In combination with pembrolizumab and platinum-based chemotherapy for first-line treatment of metastatic disease without EGFR or ALK genomic abnormalities - In combination with cisplatin for first-line treatment of locally advanced or metastatic disease - For maintenance therapy of locally advanced or metastatic disease that has not progressed after 4 cycles of platinum-based chemotherapy - For metastatic disease that has relapsed after prior chemotherapy - For second-line monotherapy in patients with locally advanced or metastatic non-squamous non-small cell lung cancer Malignant pleural mesothelioma - In combination with cisplatin for first-line treatment of patients with malignant pleural mesothelioma. In the United States, this drug is indicated only for patients who are unresectable or unsuitable for radical surgery.
FDA Label
Malignant pleural mesothelioma: Pemetrexed Accord in combination with cisplatin is indicated for the treatment of patients with unresectable malignant pleural mesothelioma who have not received chemotherapy. Non-small cell lung cancer (NSCLC): Pemetrexed (Accord) in combination with cisplatin is indicated for first-line treatment of locally advanced or metastatic NSCLC (excluding squamous cell carcinoma). Pemetrexed (Accord) monotherapy is indicated for maintenance therapy in patients with locally advanced or metastatic NSCLC (excluding squamous cell carcinoma) whose disease has not progressed immediately after platinum-based chemotherapy. Pemetrexed (Accord) is indicated for second-line monotherapy in patients with locally advanced or metastatic NSCLC (non-squamous cell predominant histological type). Malignant pleural mesothelioma: Pemetrexed (Accord) in combination with cisplatin is indicated for the treatment of patients with unresectable malignant pleural mesothelioma who have not undergone chemotherapy. Non-small cell lung cancer (NSCLC): Pemetrexed (Accord) in combination with cisplatin is indicated for first-line treatment of patients with locally advanced or metastatic NSCLC (non-squamous cell predominant histological type). Pemetrexed monotherapy is indicated for maintenance therapy in patients with locally advanced or metastatic NSCLC (non-squamous cell predominant histological type), and is indicated for patients whose disease has not progressed immediately after platinum-based chemotherapy. Pemetrexed is indicated as second-line monotherapy for patients with locally advanced or metastatic non-small cell lung cancer (non-squamous cell predominant histological type). Malignant pleural mesothelioma: Pemetrexed (Krka) in combination with cisplatin is indicated for the treatment of patients with unresectable malignant pleural mesothelioma who have not undergone chemotherapy. Non-small cell lung cancer: Pemetrexed (Krka) in combination with cisplatin is indicated as first-line therapy for patients with locally advanced or metastatic non-small cell lung cancer (non-squamous cell predominant histological type). Pemetrexed (Krka) is indicated as maintenance therapy for patients with locally advanced or metastatic non-small cell lung cancer (non-squamous cell predominant histological type) whose disease has not progressed immediately after platinum-based chemotherapy. Pemetrexed (Krka) is indicated as second-line monotherapy for patients with locally advanced or metastatic non-small cell lung cancer (non-squamous cell predominant histological type). Malignant pleural mesothelioma: Pemetrexed (Baxter) in combination with cisplatin is indicated for the treatment of patients with unresectable malignant pleural mesothelioma who have not undergone chemotherapy. Non-small cell lung cancer (NSCLC): Pemetrexed Baxter in combination with cisplatin is indicated for first-line treatment of patients with locally advanced or metastatic NSCLC (non-squamous cell-predominant histological type) (see Section 5.1). Pemetrexed Baxter is indicated for maintenance therapy of patients with locally advanced or metastatic NSCLC (non-squamous cell-predominant histological type) whose disease has not progressed immediately after platinum-based chemotherapy (see Section 5.1). Pemetrexed Baxter is indicated for second-line monotherapy of patients with locally advanced or metastatic NSCLC (excluding squamous cell carcinoma) (see Section 5.1). Malignant pleural mesothelioma: Pemetrexed Pfizer in combination with cisplatin is indicated for the treatment of patients with unresectable malignant pleural mesothelioma who have not undergone chemotherapy. Non-small cell lung cancer (NSCLC): Pemetrexed Pfizer in combination with cisplatin is indicated for first-line treatment of patients with locally advanced or metastatic NSCLC (excluding squamous cell carcinoma). Pemetrexed (Pfizer) is indicated for maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer (excluding squamous cell carcinoma) whose disease has not progressed immediately after platinum-based chemotherapy. Pemetrexed (Pfizer) is indicated for second-line monotherapy in patients with locally advanced or metastatic non-small cell lung cancer (excluding squamous cell carcinoma). Malignant pleural mesothelioma: Ciambra in combination with cisplatin is used for the treatment of patients with unresectable malignant pleural mesothelioma who have not received chemotherapy. Non-small cell lung cancer: Ciambra in combination with cisplatin is used for first-line treatment in patients with locally advanced or metastatic non-small cell lung cancer (excluding squamous cell carcinoma). Ciambra is also indicated for maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer (excluding squamous cell carcinoma) whose disease has not progressed immediately after platinum-based chemotherapy. Ciambra is indicated for second-line monotherapy in patients with locally advanced or metastatic non-small cell lung cancer (excluding squamous cell carcinoma). Malignant pleural mesothelioma: Pemetrexed in combination with cisplatin is indicated for the treatment of patients with unresectable malignant pleural mesothelioma who have not received chemotherapy. Non-small cell lung cancer (NSCLC): Pemetrexed in combination with cisplatin is indicated for first-line treatment of patients with locally advanced or metastatic NSCLC (excluding squamous cell carcinoma). Pemetrexed monotherapy is indicated for maintenance therapy of patients with locally advanced or metastatic NSCLC (excluding squamous cell carcinoma), and is suitable for patients whose disease has not progressed immediately after platinum-based chemotherapy. Pemetrexed Medac is indicated for second-line monotherapy of patients with locally advanced or metastatic NSCLC (non-squamous cell-predominant histological type). Malignant pleural mesothelioma: Pemetrexed Sandoz in combination with cisplatin is indicated for the treatment of patients with unresectable malignant pleural mesothelioma who have not undergone chemotherapy. Non-small cell lung cancer (NSCLC): Pemetrexed Sandoz in combination with cisplatin is indicated for first-line treatment of patients with locally advanced or metastatic NSCLC (non-squamous cell-predominant histological type). Pemetrexed Sandoz is indicated for maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer (non-squamous predominant histological type) whose disease has not progressed immediately after platinum-based chemotherapy. Pemetrexed Sandoz is also indicated for second-line monotherapy in patients with locally advanced or metastatic non-small cell lung cancer (non-squamous predominant histological type). Malignant pleural mesothelioma: Pemetrexed Fresenius Kabi in combination with cisplatin is indicated for the treatment of patients with unresectable malignant pleural mesothelioma who have not undergone chemotherapy. Non-small cell lung cancer: Pemetrexed Fresenius Kabi in combination with cisplatin is indicated for first-line treatment in patients with locally advanced or metastatic non-small cell lung cancer (non-squamous predominant histological type). Pemetrexed Fresenius Kabi is also indicated for maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer (non-squamous predominant histological type) whose disease has not progressed immediately after platinum-based chemotherapy. Pemetrexed (Fresenius Kabi) is indicated for second-line monotherapy in patients with locally advanced or metastatic non-small cell lung cancer (excluding squamous cell carcinoma). Malignant pleural mesothelioma: Pemetrexed in combination with cisplatin is indicated for the treatment of patients with unresectable malignant pleural mesothelioma who have not undergone chemotherapy. Non-small cell lung cancer: Pemetrexed in combination with cisplatin is indicated for first-line treatment in patients with locally advanced or metastatic non-small cell lung cancer (excluding squamous cell carcinoma). Pemetrexed is indicated for maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer (excluding squamous cell carcinoma) whose disease has not progressed immediately after platinum-based chemotherapy. Alimta is indicated for second-line monotherapy in patients with locally advanced or metastatic non-small cell lung cancer (non-squamous cell-predominant histological type). Malignant pleural mesothelioma: Pemetrexed (Eli Lilly) in combination with cisplatin is indicated for the treatment of patients with unresectable malignant pleural mesothelioma who have not undergone chemotherapy. Non-small cell lung cancer (NSCLC): Pemetrexed (Eli Lilly) in combination with cisplatin is indicated for first-line treatment of patients with locally advanced or metastatic NSCLC (non-squamous cell predominant histological type). Pemetrexed (Eli Lilly) is indicated for maintenance treatment of patients with locally advanced or metastatic NSCLC (non-squamous cell predominant histological type) whose disease has not progressed immediately after platinum-based chemotherapy. Pemetrexed (Eli Lilly) is indicated for second-line monotherapy in patients with locally advanced or metastatic NSCLC (excluding squamous cell carcinoma). Malignant pleural mesothelioma: Pemetrexed (Hospira UK Limited) in combination with cisplatin is indicated for the treatment of patients with unresectable malignant pleural mesothelioma who have not undergone chemotherapy. Non-small cell lung cancer (NSCLC): Pemetrexed (Hospira UK Limited) in combination with cisplatin is indicated for first-line treatment of patients with locally advanced or metastatic NSCLC (excluding squamous cell carcinoma) (see Section 5.1 of the drug information leaflet). Pemetrexed, manufactured by Hospira (UK), is indicated for maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer (non-squamous predominant histological type) whose disease has not progressed immediately after platinum-based chemotherapy (see Section 5.1 of the drug package insert). Pemetrexed, also manufactured by Hospira (UK), is also indicated for second-line treatment in patients with locally advanced or metastatic non-small cell lung cancer (non-squamous predominant histological type) (see Section 5.1 of the drug package insert). Mechanism of Action Pemetrexed is an antifolate drug containing a pyrrolopyrimidine nucleus. It exerts its antitumor activity by interfering with folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycine nucleotide formyltransferase (GARFT), all of which are folate-dependent enzymes involved in the de novo synthesis of thymidine and purine nucleotides. Pemetrexed enters cells via reduced folate carriers and the membrane folate-binding protein transport system. Once inside the cell, pemetrexed is converted to its polyglutamate form by folate polyglutamate synthase. The polyglutamate form remains intracellularly and inhibits the activity of TS and GARFT. Polyglutamate synthesis is a time- and concentration-dependent process, primarily occurring in tumor cells, but also in small amounts in normal tissues. The polyglutamate metabolite has a longer intracellular half-life, thus prolonging the drug's duration of action in malignant cells. Pemetrexed is an antifolate drug containing a pyrrolopyrimidine nucleus that exerts its antitumor activity by interfering with folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidine synthase (TS), dihydrofolate reductase (DHFR), and glycine ribonucleotide formyltransferase (GARFT), all of which are folate-dependent enzymes involved in the de novo synthesis of thymidine and purine nucleotides. Pemetrexed enters cells via reduced folate carriers and the membrane folate-binding protein transport system. Once inside the cell, pemetrexed is converted to its polyglutamate form by folate polyglutamate synthase. These polyglutamate forms remain intracellularly and inhibit thymidylate synthase (TS) and GARFT enzymes. Polyglutamate synthesis is a time- and concentration-dependent process, primarily occurring in tumor cells, but also in small amounts in normal tissues. The prolonged intracellular half-life of polyglutamate metabolites prolongs the drug's duration of action in malignant cells. ...In cases of high cellular resistance to other thymidylate synthase inhibitors, pemetrexed activity may be partially retained, possibly due to its secondary inhibition of purine synthesis. ...Intracellular native folate competes with pemetrexed for folate polyglutamate synthase activity, thereby modulating pemetrexed activity. Impaired reduced folate carrier transport leads to methotrexate resistance, but these cells may still retain partial sensitivity to pemetrexed. This is because the transport of physiologically reduced folate decreases simultaneously, causing the intracellular folate pool to shrink, thereby relaxing the normally inhibiting levels of pemetrexed polyglutamate transformation. When intracellular folate levels are insufficient, the risk of pemetrexed toxicity increases.

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.)