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药品详细

Pralatrexate(针对pralatrexate)

化学结构式图
中文名
针对pralatrexate
英文名
Pralatrexate
分子式
C23H23N7O5
化学名
(2S)-2-({4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]phenyl}formamido)pentanedioic acid
分子量
Average: 477.4726
Monoisotopic: 477.176066881
CAS号
146464-95-1
ATC分类
L01B 抗代谢药
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

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.

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    参考
    Synthesis Reference Not Available
    General Reference
    1. Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. Pubmed
    2. Gonen N, Assaraf YG: Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210. doi: 10.1016/j.drup.2012.07.002. Epub 2012 Aug 23. Pubmed
    3. Rodd AL, Ververis K, Karagiannis TC: Safety and efficacy of pralatrexate in the management of relapsed or refractory peripheral T-cell lymphoma. Clin Med Insights Oncol. 2012;6:305-14. doi: 10.4137/CMO.S8536. Epub 2012 Aug 21. Pubmed
    剂型
    规格
    化合物类型
    Type small molecule
    Classes Not Available
    Substructures Not Available
    适应症
    药理
    Indication Treatment of relapsed or refractory peripheral T-cell lymphoma.
    Pharmacodynamics 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
    Mechanism of action 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.
    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.
    Toxicity Mucositis is the dose-limiting toxicity. Folic acid and vitamin B12 supplements do not prevent mucositis from happening.
    Affected organisms
    • Humans and other mammals
    Pathways Not Available
    理化性质
    Properties
    State solid
    Experimental Properties Not Available
    Predicted Properties
    Property Value Source
    water solubility 1.78e-02 g/l ALOGPS
    logP 0.1 ALOGPS
    logP 0.33 ChemAxon
    logS -4.4 ALOGPS
    pKa (strongest acidic) 3.44 ChemAxon
    pKa (strongest basic) 2.86 ChemAxon
    physiological charge -2 ChemAxon
    hydrogen acceptor count 11 ChemAxon
    hydrogen donor count 5 ChemAxon
    polar surface area 207.3 ChemAxon
    rotatable bond count 10 ChemAxon
    refractivity 126.82 ChemAxon
    polarizability 47.31 ChemAxon
    药物相互作用
    Drug Interaction
    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.
    食物相互作用
    Not Available

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