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Mol Pharm. 2011 Oct 3;8(5):1619-28. doi: 10.1021/mp200092v. Epub 2011 Aug 15.

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

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1
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.

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.

PMID:
21805990
PMCID:
PMC3185113
DOI:
10.1021/mp200092v
[Indexed for MEDLINE]
Free PMC Article
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