Metabolizing enzyme toxicology assay chip (MetaChip) for high-throughput microscale toxicity analyses
- *Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180; and †Department of Chemical Engineering, University of California, Berkeley, CA 94720
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Edited by Arnold L. Demain, Drew University, Madison, NJ, and approved December 2, 2004 (received for review September 11, 2004)
Abstract
The clinical progression of new chemical entities to pharmaceuticals remains hindered by the relatively slow pace of technology development in toxicology and clinical safety evaluation, particularly in vitro approaches, that can be used in the preclinical and early clinical phases of drug development. To alleviate this bottle-neck, we have developed a metabolizing enzyme toxicology assay chip (MetaChip) that combines high-throughput P450 catalysis with cell-based screening on a microscale platform. The MetaChip concept is demonstrated by using sol-gel encapsulated P450s to activate the prodrug cyclophosphamide, which is the major constituent of the anticancer drug Cytoxan, as well as other compounds that are activated by P450 metabolism. The MetaChip provides a high-throughput microscale alternative to currently used in vitro methods for human metabolism and toxicology screening based on liver slices, cultured human hepatocytes, purified microsomal preparations, or isolated and purified P450s. This technology creates opportunities for rapid and inexpensive assessment of ADME/Tox (absorption, distribution, metabolism, excretion/toxicology) at very early phases of drug development, thereby enabling unsuitable candidates to be eliminated from consideration much earlier in the drug discovery process.
Footnotes
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↵ ¶ To whom correspondence may be addressed. E-mail: dordick{at}rpi.edu or clark{at}cchem.berkeley.edu.
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↵ ‡ Present address: Department of Chemical and Materials Engineering, Arizona State University, Tempe, AZ 85287.
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↵ § J.S.D. and D.S.C. have potential financial interest in this work; they are cofounders of Solidus Biosciences, which has licensed technology related to the subject matter presented here.
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Author contributions: J.S.D. and D.S.C. designed research; M.-Y.L. and C.B.P. performed research; and M.-Y.L., J.S.D., and D.S.C. wrote the paper.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: CP, cyclophosphamide; MTMOS, methyltrimethoxysilane; 4-OH-CP, 4-hydroxycyclophosphamide.
- Copyright © 2005, The National Academy of Sciences
