Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery

被引：342

作者：

Alavijeh M.S. ^{[1
]}

Chishty M. ^{[1
]}

Qaiser M.Z. ^{[1
]}

Palmer A.M. ^{[1
,2
]}

机构：

[1] Pharmidex

[2] Pharmidex, London W1S 1RR

来源：

NeuroRX | 2005年 / 2卷 / 4期

关键词：

Aging; Blood-brain barrier; Brain disorders; CNS drug discovery; DMPK; in silico prediction of brain permeation; MDCK cells; Microdialysis; Pharmacodynamics; Pharmacokinetics;

D O I：

10.1602/neurorx.2.4.554

中图分类号：

学科分类号：

摘要：

The worldwide market for therapies for CNS disorders is worth more than $50 billion and is set to grow substantially in the years ahead. This is because: 1) the incidence of many CNS disorders (e.g., Alzheimer's disease, stroke, and Parkinson's disease) increase exponentially after age 65 and 2) the number of people in the world over 65 is about to increase sharply because of a marked rise in fertility after World War II. However, CNS research and development are associated with significant challenges: it takes longer to get a CNS drug to market (12-16 years) compared with a non-CNS drug (10-12 years) and there is a higher attrition rate for CNS drug candidates than for non-CNS drug candidates. This is attributable to a variety of factors, including the complexity of the brain, the liability of CNS drugs to cause CNS side effects, and the requirement of CNS drugs to cross the blood-brain barrier (BBB). This review focuses on BBB penetration, along with pharmacokinetics and drug metabolism, in the process of the discovery and development of safe and effective medicines for CNS disorders. © The American Society for Experimental NeuroTherapeutics, Inc.

引用

页码：554 / 571

页数：17

共 98 条

[1]

Palmer A.M., DeKosky S.T., Neurochemistry of ageing, Principles and Practice of Geriatric Medicine, pp. 65-76, (1998)

[2]

Is the pharma industry weathering the 'perfect storm'?, IMS Health, (2003)

[3]

Philips S.P., Mackintosh A., Beyond 2005. The Future of Pharmaceutical Marketing and Sale. Perspective on Life Sciences. Special Edition, (2002)

[4]

Sneader W., Drug Discovery - A History, (2005)

[5]

Snyder S.H., Drugs and the Brain, (1996)

[6]

Mannhold R., The impact of lipophilicity in drug research: A case report on β-blockers, Mini Rev Med Chem, 5, pp. 197-205, (2005)

[7]

Bergstrom C.A., In silico predictions of drug solubility and permeability: Two rate-limiting barriers to oral drug absorption, Basic Clin Pharmacol Toxicol, 96, pp. 156-161, (2005)

[8]

Avdeef A., Physicochemical profiling (solubility, permeability and charge state), Curr Top Med Chem, 1, pp. 277-351, (2001)

[9]

Riley R.J., Parker A.J., Trigg S., Manners C.N., Development of a generalized, quantitative physicochemical model of CYP3A4 inhibition for use in early drug discovery, Pharm Res, 18, pp. 652-655, (2001)

[10]

Van De Waterbeemd H., Which in vitro screens guide the prediction of oral absorption and volume of distribution?, Basic Clin Pharmacol Toxicol, 96, pp. 162-166, (2005)

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