ADME

ADME是藥代動力學和藥理學中「吸收（Absorption）、分佈（Distribution）、代謝（Metabolism）和排泄（Excretion）」的英文首字母縮寫，描述了藥物化合物在生物體內的處置（disposition）的動態變化。^[1]這四個因素均影響着藥物水平和藥物組織暴露動力學，從而影響化合物作為藥物的藥效和藥理活性^[2]。若需兼顧藥物釋放（Liberation）和/或藥物毒性（Toxicity），則會合稱為LADME、ADMET或LADMET。^[3]

組成

藥物吸收/給藥

若要將化合物送達特定組織，化合物需要先進入血液中——通常化合物經消化道等粘膜表面（腸道吸收），才會到達靶細胞。^[4]化合物的溶解度、胃排空時間、腸道轉運時間、化學性質穩定性以及消化道滲透性等因素均會降低口服給藥的藥物吸收程度，即口服生物利用度。吸收可以決定化合物的生物利用度，一種口服生物利用度不佳的藥物，則通常需要以一些較差順應性的方式給藥，如靜脈注射給藥或吸入給藥（例如扎那米韋）。給藥途徑在藥物設計中是重要的考量因素之一^[5]。

藥物分佈

藥物化合物通常經過血液被轉運至起效部位，經血液化合物可程度不同地分佈至肌肉和人體器官中。在經血管注射或從各種細胞外吸收進入體循環後，藥物需經歷各種分佈過程，而這個過程同時會降低血漿中的藥物濃度。

藥物分佈定義為藥物在一個室到另一個室的可逆轉運。影響藥物分佈的一些因素包括：局部血液流速、分子體積、分子極性和與血漿蛋白結合率。在某些體內屏障（例如血腦屏障）中，藥物分佈是一個關鍵考量因素。^[6]^[7]

藥物代謝

化合物從進入人體即開始分解。大多數小分子藥物經由肝臟通過氧化還原酶（稱為細胞色素P450酶）發生代謝過程。隨着藥物體內代謝的發生，初始（母）化合物被轉化為代謝產物的新化合物。當代謝物呈現藥理惰性時，代謝可能會使母藥（化合物）在給藥劑量下失活並降低化合物在人體內活性。代謝物也可能具有藥理活性，甚至比母藥更具藥理活性（參見前體藥物）^[8]。

藥物排泄

化合物及其代謝物需要通過排泄過程從體內清除，通常可經腎臟（尿液）或腸道（糞便）清除。若排泄過程不充分，外源性藥物會在體內積聚並對正常的新陳代謝產生不利影響。

藥物排泄主要經由三個人體器官進行。腎臟是化合物（藥物）經由尿液排出體外的器官，同樣也是最重要藥物排泄器官。膽汁排泄或糞便排泄是化合物從肝臟開始代謝並經腸道最終與糞便一起排出的過程。另一種排泄途徑是通過肺（例如麻醉氣體）進行。^[9]

經腎臟排泄藥物涉及3個主要機制^[10]：

非結合藥物通過腎小球濾過。
通過轉運體主動分泌游離藥物或蛋白結合藥物。轉運體包括陰離子轉運體（如尿酸鹽、青黴素、葡糖苷酸、硫酸結合物）和陽離子轉運體（如膽鹼、組胺）。
藥物在腎小管經濃縮至原濃度100倍以獲得對排泄更有利的濃度梯度，從而經被動擴散分泌並通過尿液排出。^[11]

藥物毒性

通常藥物設計會考量化合物的潛在或實際毒性（ADME-Tox或ADMET）。用於表徵毒性的參數包括：半數致死劑量（LD ₅₀）和治療指數^[12]。

計算化學家試圖通過QSPR或QSAR等手段預測化合物的ADME-Tox性質。^[13]

給藥途徑可大幅影響ADME性質。^[14]

參見

參考文獻

^ Di, Li; Kerns, Edward H. Profiling drug-like properties in discovery research. Current Opinion in Chemical Biology. 2003-06-01, 7 (3): 402–408 [2023-05-08]. ISSN 1367-5931. doi:10.1016/S1367-5931(03)00055-3 （英語）.
^ Tetko IV, Bruneau P, Mewes HW, Rohrer DC, Poda GI. Can we estimate the accuracy of ADME-Tox predictions? (PDF). Drug Discovery Today. August 2006, 11 (15–16): 700–707 [2023-05-02]. PMID 16846797. doi:10.1016/j.drudis.2006.06.013. （原始內容 (pre-print)存檔於2013-09-12）.
^ Edward HK, Li D. Druglike Properties: Concepts Structure Design and Methods from ADME to Toxicity Optimization. August 2008. doi:10.1016/C2013-0-18378-X.
^ van de Waterbeemd, Han; Smith, Dennis A.; Beaumont, Kevin; Walker, Don K. Property-Based Design: Optimization of Drug Absorption and Pharmacokinetics. Journal of Medicinal Chemistry. 2001-04-01, 44 (9): 1313–1333 [2023-05-08]. ISSN 0022-2623. doi:10.1021/jm000407e. （原始內容存檔於2022-09-28）（英語）.
^ Balani SK, Miwa GT, Gan LS, Wu JT, Lee FW. Strategy of utilizing in vitro and in vivo ADME tools for lead optimization and drug candidate selection. Current Topics in Medicinal Chemistry. 2005, 5 (11): 1033–1038. PMID 16181128. doi:10.2174/156802605774297038.
^ Di, Li; Rong, Haojing; Feng, Bo. Demystifying Brain Penetration in Central Nervous System Drug Discovery: Miniperspective. Journal of Medicinal Chemistry. 2013-01-10, 56 (1): 2–12 [2023-05-08]. ISSN 0022-2623. doi:10.1021/jm301297f. （原始內容存檔於2022-02-24）（英語）.
^ Golden, Pamela L.; Pollack, Gary M. Blood–Brain Barrier Efflux Transport. Journal of Pharmaceutical Sciences. 2003-09-01, 92 (9): 1739–1753 [2023-05-08]. ISSN 0022-3549. doi:10.1002/jps.10424 （英語）.
^ Singh SS. Preclinical pharmacokinetics: an approach towards safer and efficacious drugs. Current Drug Metabolism. February 2006, 7 (2): 165–182. PMID 16472106. doi:10.2174/138920006775541552.
^ Leeson, Paul D.; Springthorpe, Brian. The influence of drug-like concepts on decision-making in medicinal chemistry. Nature Reviews Drug Discovery. 2007-11, 6 (11): 881–890 [2023-05-08]. ISSN 1474-1784. doi:10.1038/nrd2445. （原始內容存檔於2023-01-28）（英語）.
^ Tamai, Ikumi; Tsuji, Akira. Carrier-mediated approaches for oral drug delivery. Advanced Drug Delivery Reviews. 1996-07-12, 20 (1): 5–32 [2023-05-08]. ISSN 0169-409X. doi:10.1016/0169-409X(95)00128-T （英語）.
^ Chan, Lauretta M. S; Lowes, Simon; Hirst, Barry H. The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. European Journal of Pharmaceutical Sciences. 2004-01-01, 21 (1): 25–51 [2023-05-08]. ISSN 0928-0987. doi:10.1016/j.ejps.2003.07.003 （英語）.
^ C.D. MKlaassen, Principles of toxicology and treatment of poisoning, in： L. L. Brunton(Ed.), Goodman and Gillman's The Pharmacological Basis of Therapeutics,11th ed., McGraw-Hill, New York, 2006, pp. 1739-1751.
^ Li, Albert P. Screening for human ADME/Tox drug properties in drug discovery. Drug Discovery Today. 2001-04-01, 6 (7): 357–366 [2023-05-08]. ISSN 1359-6446. doi:10.1016/S1359-6446(01)01712-3 （英語）.
^ Research, Center for Drug Evaluation and. M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. U.S. Food and Drug Administration. 2020-04-24 [2023-05-10]. （原始內容存檔於2023-03-27）（英語）.

[1] Di, Li; Kerns, Edward H. Profiling drug-like properties in discovery research. Current Opinion in Chemical Biology. 2003-06-01, 7 (3): 402–408 [2023-05-08]. ISSN 1367-5931. doi:10.1016/S1367-5931(03)00055-3 （英語）.

[2] Tetko IV, Bruneau P, Mewes HW, Rohrer DC, Poda GI. Can we estimate the accuracy of ADME-Tox predictions? (PDF). Drug Discovery Today. August 2006, 11 (15–16): 700–707 [2023-05-02]. PMID 16846797. doi:10.1016/j.drudis.2006.06.013. （原始內容 (pre-print)存檔於2013-09-12）.

[3] Edward HK, Li D. Druglike Properties: Concepts Structure Design and Methods from ADME to Toxicity Optimization. August 2008. doi:10.1016/C2013-0-18378-X.

[4] van de Waterbeemd, Han; Smith, Dennis A.; Beaumont, Kevin; Walker, Don K. Property-Based Design: Optimization of Drug Absorption and Pharmacokinetics. Journal of Medicinal Chemistry. 2001-04-01, 44 (9): 1313–1333 [2023-05-08]. ISSN 0022-2623. doi:10.1021/jm000407e. （原始內容存檔於2022-09-28）（英語）.

[5] Balani SK, Miwa GT, Gan LS, Wu JT, Lee FW. Strategy of utilizing in vitro and in vivo ADME tools for lead optimization and drug candidate selection. Current Topics in Medicinal Chemistry. 2005, 5 (11): 1033–1038. PMID 16181128. doi:10.2174/156802605774297038.

[6] Di, Li; Rong, Haojing; Feng, Bo. Demystifying Brain Penetration in Central Nervous System Drug Discovery: Miniperspective. Journal of Medicinal Chemistry. 2013-01-10, 56 (1): 2–12 [2023-05-08]. ISSN 0022-2623. doi:10.1021/jm301297f. （原始內容存檔於2022-02-24）（英語）.

[7] Golden, Pamela L.; Pollack, Gary M. Blood–Brain Barrier Efflux Transport. Journal of Pharmaceutical Sciences. 2003-09-01, 92 (9): 1739–1753 [2023-05-08]. ISSN 0022-3549. doi:10.1002/jps.10424 （英語）.

[8] Singh SS. Preclinical pharmacokinetics: an approach towards safer and efficacious drugs. Current Drug Metabolism. February 2006, 7 (2): 165–182. PMID 16472106. doi:10.2174/138920006775541552.

[9] Leeson, Paul D.; Springthorpe, Brian. The influence of drug-like concepts on decision-making in medicinal chemistry. Nature Reviews Drug Discovery. 2007-11, 6 (11): 881–890 [2023-05-08]. ISSN 1474-1784. doi:10.1038/nrd2445. （原始內容存檔於2023-01-28）（英語）.

[10] Tamai, Ikumi; Tsuji, Akira. Carrier-mediated approaches for oral drug delivery. Advanced Drug Delivery Reviews. 1996-07-12, 20 (1): 5–32 [2023-05-08]. ISSN 0169-409X. doi:10.1016/0169-409X(95)00128-T （英語）.

[11] Chan, Lauretta M. S; Lowes, Simon; Hirst, Barry H. The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. European Journal of Pharmaceutical Sciences. 2004-01-01, 21 (1): 25–51 [2023-05-08]. ISSN 0928-0987. doi:10.1016/j.ejps.2003.07.003 （英語）.

[12] C.D. MKlaassen, Principles of toxicology and treatment of poisoning, in： L. L. Brunton(Ed.), Goodman and Gillman's The Pharmacological Basis of Therapeutics,11th ed., McGraw-Hill, New York, 2006, pp. 1739-1751.

[13] Li, Albert P. Screening for human ADME/Tox drug properties in drug discovery. Drug Discovery Today. 2001-04-01, 6 (7): 357–366 [2023-05-08]. ISSN 1359-6446. doi:10.1016/S1359-6446(01)01712-3 （英語）.

[14] Research, Center for Drug Evaluation and. M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. U.S. Food and Drug Administration. 2020-04-24 [2023-05-10]. （原始內容存檔於2023-03-27）（英語）.

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