阿托伐他汀
阿托伐他汀(英語:),商品名为立普妥(Lipitor),是降低血液胆固醇水平的常见药物。由輝瑞公司裝造。[1]。它是一種他汀類藥物,用於降低血液中的膽固醇。它還可穩定血液斑塊和預防中風。类似于所有他汀類藥物,阿托伐他汀通過抑制肝組織中,一種對膽固醇製造起關鍵作用的酵素——羟甲基戊二酸单酰辅酶A还原酶(HMG-CoA reductase),以減少體內製造膽固醇。
系统(IUPAC)命名名称 | |
---|---|
(3R,5R)-7-[2-(4-Fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid | |
临床数据 | |
商品名 | Lipitor, Atorva |
Drugs.com | Monograph |
MedlinePlus | a600045 |
医疗法规 |
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妊娠分级 | |
给药途径 | 口服 |
合法狀態 | |
合法状态 |
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药代动力学数据 | |
生物利用度 | 12% |
代谢 | 肝脏 - CYP3A4 |
生物半衰期 | 14小时 |
排泄 | 胆汁 |
识别 | |
CAS注册号 | 134523-00-5 |
ATC代码 | C10AA05 |
PubChem | CID 60823 |
IUPHAR/BPS | 2949 |
DrugBank | APRD00055 |
ChemSpider | 54810 |
UNII | A0JWA85V8F |
KEGG | D07474 |
ChEBI | CHEBI:39548 |
ChEMBL | CHEMBL1487 |
PDB配体ID | 117 (PDBe, RCSB PDB) |
化学 | |
化学式 | C33H35FN2O5 |
摩尔质量 | 558.64 |
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阿托伐他汀於1985年由布魯斯·羅斯-帕克-戴維斯華納-蘭伯特公司(Bruce Roth of Parke-Davis Warner-Lambert Company)首次合成(現為輝瑞公司/Pfizer),是製藥歷史上銷售最好的藥物。它自1996年被美國食品藥品監督管理局批准以來,累計銷售額超過1,250億美元[2],並連續保持此銷售冠軍紀錄達十年[3]。通用阿托伐他汀,由沃森製藥公司和蘭伯西實驗室製造,並於2011年11月30日開始於美國上市。
禁忌
服用阿托伐他汀期間必須注意有某些情況下可能出現橫紋肌溶解症,一種可引起肌红蛋白尿症並導致急性腎衰竭的併發症。如果被懷疑或診斷為橫紋肌溶解症,須立即停止阿托伐他汀治療[30]。但實驗顯示,阿托伐他汀可能起到保護腎功能的作用[31]。另外,如果病人肌酸激酶(Creatine kinase,CK)的水平明顯升高和懷疑有肌病,也應停止使用阿托伐他汀。當與環孢素、貝特類(Fibrate)藥物、紅黴素、烟酸或唑類抗真菌药共同給藥有可能增加導致肌病的風險。[29]
在懷孕期間是絕對禁止使用阿托伐他汀的,因為膽固醇是胎兒發育的必須生物合成途徑,也包括類固醇和細胞膜生成。另外也不建議餵哺母乳者服用此藥,因為通過老鼠的實驗表明阿托伐他汀可能會進入人類的乳汁分泌。[29]
副作用
阿托伐他汀最嚴重副作用為肌酸激酶(CK)升高導致的肌病和橫紋肌溶解症,雖然發生機會低於1%。[32][29]頭痛是最常見的副作用,發生在10%的患者上。
其他副作用(發生機率在1–10%之間)包括:無力、失眠和頭暈、胸部疼痛和外週性水腫、皮疹、腹痛、便秘、腹瀉、消化不良、胃腸脹氣、噁心、泌尿道感染、關節痛、肌肉痛、背痛、關節炎、鼻竇炎、咽炎、支氣管炎、鼻炎、感染、流感樣綜合徵和過敏性反應。[29]
小部分服用本藥和/或其它他汀類藥物病者曾引致失憶,特別是女性。因膽固醇的合成,是正常的神經元功能所必需的。但據輝瑞公司的臨床試驗,“膽固清沒有和失憶之間有因果關係。[33][34][35]
在少數情況下,谷丙转氨酶(ALT)和天冬氨酸氨基转移酶(AST)水平會升高。[36]。
有報告指出高劑量阿托伐他汀能使血糖控制惡化。[37]
藥物和食物的相互作用
此藥物和安妥明(Clofibrate)、非諾貝特(Fenofibrate)、吉非貝齊(Gemfibrozil)(一些治療高膽固醇血症藥物)有相互作用,可增加引致肌病和橫紋肌溶解症風險。[38][39]
和CYP3A4抑制劑(伊曲康唑,泰利和伏立康唑)共同用藥,可能會導致不良反應。和CYP3A4誘導劑(波生坦,磷苯妥英鈉,苯妥英)聯合用藥,可能減少阿托伐他汀的血液濃度。烟酸也被證明增加肌病或橫紋肌溶解症的風險。他汀也能令其他藥物(如華法林或地高辛)的濃度發生改變。補充維生素D可降低阿托伐他汀和活性代謝物濃度。
葡萄柚汁是腸道CYP3A4的抑制劑,葡萄柚汁與阿托伐他汀共服可能會導致Cmax和AUC增加,從而導致不良反應或藥物過量並產生毒性。[40][41][42][43]
作用機理
阿托伐他汀是HMG-CoA還原酶的競爭性抑制劑,這與其他他汀類藥物相似,但不同的是本藥為一個完全人工合成的化合物。 HMG-CoA還原酶催化還原3-羥基-3-甲基-輔酶A(HMG-COA)成為甲羟戊酸,這是肝臟膽固醇生物合成的速率控制步驟(rate-limiting step)。通過抑制這種酵素,降低从头合成膽固醇,增加肝細胞上的低密度脂蛋白受體(LDL受體),增加肝細胞對低密度脂蛋白的吸收,降低血液中的低密度脂蛋白膽固醇量。像其他他汀類藥物,阿托伐他汀也降低血液三酸甘油酯水平,並略有增加高密度脂蛋白膽固醇水平。
藥代動力學
口服阿托伐他汀吸收迅速,最大血藥濃度1至2小時。該藥物的絕對生物利用度約為14%。阿托伐他汀通過腸道時經歷首过效应,這是此藥的生物利用度低的主要原因。儘管當阿托伐他汀與食物一起服用時,其降低血液LDL(低密度脂蛋白)的效用並沒因此減少,但與食物共服,藥物Cmax(吸收率)減少25%,AUC(吸收程度)減少9%;而夜間服藥Cmax(吸收率)和AUC(吸收程度)減少30%,但都不會影響阿托伐他汀的療效。
阿托伐他汀的蛋白結合率高(≥98%),阿托伐他汀代謝主要通過細胞色素P450-3A4羥基形成。以激活鄰位類羥基化代謝物和β-氧化代謝物。前者對全身的HMG-CoA還原酶運作起關鍵效用。鄰羥基代謝物進一步透過葡糖醛酸代謝作用代謝。細胞色素P450的抑制劑和诱导剂分別能增加或減少此藥的血藥濃度,這已被一項以紅黴素(一種已知的細胞色素P450抑制劑)與阿托伐他汀為對象的實驗室試驗中被驗證。
阿托伐他汀主要是經肝膽汁排泄,阿托伐他汀在尿液中回收的不到2%,沒有進入肠肝循环。阿托伐他汀消除半衰期約14小時。值得注意的是,HMG-CoA還原酶抑制活性有半衰期20至30小時,這被認為是與活性代謝產物有關。阿托伐他汀也是腸道P-糖蛋白外排轉運,在藥物正在腸臟被吸收時被泵回腸腔中。[44]
肝功能不全患者,血藥濃度受到肝臟疾病顯著影響。與A-末期肝病患者Cmax和AUC增加4倍。B超末期肝病患者的Cmax增加16倍、AUC增加11倍。老年患者(65歲以上)藥代動力學表現與年輕成年人不同,老年患者的AUC和Cmax值分別提高40%和30%;而健康長者對藥物反應較理想,故可能只需處方較低劑量予此人群。[29][45][46]
藥理學
阿托伐他汀一些基因多態性(Genetic polymorphism)已被發現與本藥不良副作用的發生率較高有關。這種現象被懷疑與血漿中的藥理活性代謝產物增加有關,如阿托伐他汀內酯和P-Hydroxyatorvastatin。對於較可能誘發不良副作用的潛在患者,可使用特定的色譜技術對阿托伐他汀及其活性代謝物進行監測。[47]
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- He L. . Chinese Academy of Sciences·Institute of Process Engineering. 2003-09-27 [2011-10-26]. (原始内容存档于2011-07-19).
外部連結
- Atorvastatin bound to proteins in the PDB
- Lipitor.com – manufacturer's site
- MedlinePlus Drug information: Atorvastatin (Systemic) – information from USP DI Advice for the Patient
- U.S. National Library of Medicine: Drug Information Portal - Atorvastatin