Pralatrexate

Các tên gọi khác (9 ) :

(2S)-2-((4-((1RS)-1-((2,4-diaminopteridin-6-yl)methyl)but-3-ynyl)benzoyl)amino)pentanedioic acid
(2S)-2-({4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl}amino)pentanedioic acid
10-Propargyl-10-deazaaminopterin
Folotyn
HSDB 7786
N-(4-(1-((2,4-Diamino-6-pteridinyl)methyl)-3-butynyl)benzoyl)-L-glutamic acid
PDX
Pralatrexato
Pralatrexatum

Thuốc Gốc

Small Molecule

CAS: 146464-95-1

ATC: L01BA05

CTHH: C₂₃H₂₃N₇O₅

PTK: 477.4726

Pralatrexate is an antimetabolite for the treatment of relapsed or refractory peripheral T-cell lymphoma. It is more efficiently retained in cancer cells than methotrexate. FDA approved on September 24, 2009.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₂₃H₂₃N₇O₅

Phân tử khối

477.4726

Monoisotopic mass

477.176066881

InChI

InChI=1S/C23H23N7O5/c1-2-3-14(10-15-11-26-20-18(27-15)19(24)29-23(25)30-20)12-4-6-13(7-5-12)21(33)28-16(22(34)35)8-9-17(31)32/h1,4-7,11,14,16H,3,8-10H2,(H,28,33)(H,31,32)(H,34,35)(H4,24,25,26,29,30)/t14?,16-/m0/s1

InChI Key

InChIKey=OGSBUKJUDHAQEA-WMCAAGNKSA-N

IUPAC Name

(2S)-2-({4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]phenyl}formamido)pentanedioic acid

Traditional IUPAC Name

pralatrexate

SMILES

NC1=NC2=NC=C(CC(CC#C)C3=CC=C(C=C3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)N=C2C(N)=N1

Độ hòa tan

1.78e-02 g/l

logP

0.33

logS

-4.4

pKa (strongest acidic)

3.44

pKa (Strongest Basic)

2.86

PSA

207.3 Å²

Refractivity

126.82 m³·mol^-1

Polarizability

47.31 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

-2

Number of Rings

Bioavailability

Ghose Filter

true

MDDR-Like Rule

true

Dược Lực Học : Pralatrexate is a 10-deazaaminopterin analogue of methotrexate. Compared to methotrexate, pralatrexate binds to RTC-1 with 10-times the affinity and is a more potent substrate for FPGS. As a result, pralatrexate is better internalized and retained in cancer cells and is more cytotoxic. Km, pralatrexate = 0.3 μmol/L; Km, methotrexate = 4.8 μmol/L; Vmax/Km (rate of intracellular transport), pralatrexate = 12.6 Vmax/Km (rate of intracellular transport), methotrexate = 0.9

Cơ Chế Tác Dụng : Pralatrexate is an antimetabolite for the treatment of relapsed or refractory peripheral T-cell lymphoma. It is more efficiently retained in cancer cells than methotrexate. FDA approved on September 24, 2009. The selectivity of pralatrexate for cancer cells is based upon the observation that cancer cells generally have an overexpression of reduced folate carrier protein-1 (RTC-1) compared to normal somatic cells. This carrier protein allows the entrance of pralatrexate into the cell. Upon entering the cell, folypolyglutamate synthase FPGS catalyzes the polyglutamination of pralatrexate so that it is retained inside the cell. Once inside, pralatrexate competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase. Subsequent depletion of thymidine monophosphate (TMP) occurs so that the cancer cell is unable to synthesize DNA and RNA. As a result, the cancer cell cannot proliferate and is forced to undergo apoptosis. Pralatrexate is more effective against cells that are actively dividing.

Dược Động Học :

▧ Absorption :
Pralatrexate demonstrates linear pharmacokinetics with a multiphasic decline with both diasteromers over dose range of 30-325 mg/m^2. Bioavailability, nonformulated preparation = 13 - 20%
▧ Volume of Distribution :
Vss, R-pralatrexate = 37 L Vss, S-pralatrexate = 105 L
▧ Protein binding :
67 - 86% bound to plasma protein, albumin is the major binder. Does not significantly displace substrates from proteins.
▧ Metabolism :
No involvement of CYP450 enzyme system or glucuronidases.
▧ Route of Elimination :
35% of drug is excreted unchanged in the urine (no difference between R- and S- pralatrexate). May be some net renal tubular excretion.
▧ Half Life :
12-18 hours
▧ Clearance :
R- pralatrexate = 191 mL/min S- pralatrexate = 417 mL/min Mean clearance of both enantiomers is 220 mL/min.

Độc Tính : Mucositis is the dose-limiting toxicity. Folic acid and vitamin B12 supplements do not prevent mucositis from happening.

Chỉ Định : Treatment of relapsed or refractory peripheral T-cell lymphoma.

Tương Tác Thuốc :

Belatacept Increased immunosuppresive effects and risk of infection. Monitor for adverse effects .
Celecoxib NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Denosumab Increased immunosuppresive effects and risk of infection. Monitor for adverse effects .
Diclofenac NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Diflunisal NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Etodolac NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Fenoprofen NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Flurbiprofen NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Ibuprofen NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Indomethacin NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Meclofenamic acid NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Meloxicam NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Nabumetone NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Naproxen NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Oxaprozin NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Palifermin Increases the toxicity of pralatrexate. Avoid concomitant therapy or do not use palifermin within 24 hours after administration of pralatrexate.
Piroxicam NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Probenecid Decreases renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects.
Sulfamethoxazole Decreases renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects.
Sulindac NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
Tolmetin NSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.

Liều Lượng & Cách Dùng : Injection, solution - Intravenous - 20 mg/mL

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : Allos Therapeutics, Inc.

Sản phẩm biệt dược : Folotyn

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB06813

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D05589

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/48818-001-01

Wikipedia

http://en.wikipedia.org/wiki/Pralatrexate

RxList

http://www.rxlist.com/folotyn-drug.htm

Drugs.com

http://www.drugs.com/cdi/pralatrexate.html

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