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J Med Chem. 2015 Aug 13;58(15):5691-8. doi: 10.1021/acs.jmedchem.5b00201. Epub 2015 Apr 1.

Volume of Distribution in Drug Design.

Author information

1
†4 The Maltings, Walmer, Kent CT14 7AR, U.K.
2
‡Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Cambridge, Massachusetts 02139, United States.
3
§Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut 06340, United States.

Abstract

Volume of distribution is one of the most important pharmacokinetic properties of a drug candidate. It is a major determinant of half-life and dosing frequency of a drug. For a similar log P, a basic molecule will tend to exhibit higher volume of distribution than a neutral molecule. Acids often exhibit low volumes of distribution. Although a design strategy against volume of distribution can be advantageous in achieving desirable dosing regimen, it must be well-directed in order to avoid detrimental effects to other important properties. Strategies to increase volume of distribution include adding lipophilicity and introducing basic functional groups in a way that does not increase metabolic clearance.

PMID:
25799158
DOI:
10.1021/acs.jmedchem.5b00201
[Indexed for MEDLINE]

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