The subcellular distribution of small molecules: from pharmacokinetics to synthetic biology.

Abstract:

:The systemic pharmacokinetics and pharmacodynamics of small molecules are determined by subcellular transport phenomena. Although approaches used to study the subcellular distribution of small molecules have gradually evolved over the past several decades, experimental analysis and prediction of cellular pharmacokinetics remains a challenge. In this review, we survey the progress of subcellular distribution research since the 1960s, with a focus on the advantages, disadvantages and limitations of the various experimental techniques. Critical review of the existing body of knowledge points to many opportunities to advance the rational design of organelle-targeted chemical agents. These opportunities include (1) development of quantitative, non-fluorescence-based, whole cell methods and techniques to measure the subcellular distribution of chemical agents in multiple compartments; (2) exploratory experimentation with nonspecific transport probes that have not been enriched with putative, organelle-targeting features; (3) elaboration of hypothesis-driven, mechanistic and modeling-based approaches to guide experiments aimed at elucidating subcellular distribution and transport; and (4) introduction of revolutionary conceptual approaches borrowed from the field of synthetic biology combined with cutting edge experimental strategies. In our laboratory, state-of-the-art subcellular transport studies are now being aimed at understanding the formation of new intracellular membrane structures in response to drug therapy, exploring the function of drug-membrane complexes as intracellular drug depots, and synthesizing new organelles with extraordinary physical and chemical properties.

journal_name

Mol Pharm

journal_title

Molecular pharmaceutics

authors

Zheng N,Tsai HN,Zhang X,Rosania GR

doi

10.1021/mp200092v

subject

Has Abstract

pub_date

2011-10-03 00:00:00

pages

1619-28

issue

5

eissn

1543-8384

issn

1543-8392

journal_volume

8

pub_type

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