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Drug Metabolism & Disposition

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Absorption, distribution, metabolism, and excretion of FDA-approved antisense oligonucleotide drugs

Julia M Migliorati, Sunna Liu, Anna Liu, Anagha Gogate, Sreenidhi Nair, Raman Bahal, Theodore P Rasmussen, Jose E. Manautou PhD and Xiao-bo Zhong
Drug Metabolism and Disposition February 27, 2022, DMD-MR-2021-000417; DOI: https://doi.org/10.1124/dmd.121.000417
Julia M Migliorati
1University of Connecticut, United States
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Sunna Liu
1University of Connecticut, United States
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Anna Liu
1University of Connecticut, United States
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Anagha Gogate
1University of Connecticut, United States
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Sreenidhi Nair
1University of Connecticut, United States
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Raman Bahal
1University of Connecticut, United States
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Theodore P Rasmussen
1University of Connecticut, United States
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Jose E. Manautou PhD
2Pharmaceutical Sciences, University of Connecticut, United States
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Xiao-bo Zhong
2Pharmaceutical Sciences, University of Connecticut, United States
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  • ORCID record for Xiao-bo Zhong
  • For correspondence: xiaobo.zhong@uconn.edu
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Abstract

Absorption, distribution, metabolism, and excretion (ADME) are the key biological processes for determination of a drug's pharmacokinetic parameters, which have direct impacts on efficacy and adverse drug reactions (ADRs). The chemical structures, dosage forms, and sites and routes of administration are the principal determinants of ADME profiles and consequent impacts on their efficacy and ADRs. Newly developed large biological antisense oligonucleotide (ASO) drugs have completely unique ADME that is not fully defined. ASO-based drugs are single-stranded synthetic antisense nucleic acids with diverse modes of drug actions from induction of mRNA degradation, exon skipping and restoration, and interactions with proteins. ASO drugs have a great potential to treat certain human diseases that have remained untreatable with small molecule-based drugs. The ADME of ASO drugs contributes to their unique set of ADRs and toxicity. In this review, to better understand their ADME, the ten FDA-approved ASO drugs were selected, including Fomivirsen, Pegaptanib, Mipomersen, Nusinersen, Inotersen, Defibrotide, Eteplirsen, Golodirsen, Viltolarsen, and Casimersen. A meta-analysis was conducted on their formulation, dosage, sites of administration, local and systematic distribution, metabolism, degradation, and excretion. Membrane permeabilization through endocytosis and nucleolytic degradation by endonucleases and exonucleases are major ADME features of the ASO drugs differing from small-molecule drugs. The information summarized here provides comprehensive ADME characteristics of FDA-approved ASO drugs, leading to a better understanding of their therapeutic efficacy and their potential ADRs and toxicity. Numerous knowledge gaps, particularly on cellular uptake and subcellular trafficking and distribution are identified, and future perspectives and directions are discussed.

Significance Statement Through a systematic analysis of the existing information of ADME parameters for ten FDA-approved ASO drugs, this review provides an overall view of the unique ADME characteristics of ASO drugs, which are distinct from small chemical drug ADME. This knowledge is useful for discovery and development of new ASO drugs as well as clinical use of current FDA-approved ASO drugs.

  • ADME
  • antisense oligonucleotides
  • drug toxicity
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 51 (2)
Drug Metabolism and Disposition
Vol. 51, Issue 2
1 Feb 2023
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ADME of FDA-approved ASO drugs

Julia M Migliorati, Sunna Liu, Anna Liu, Anagha Gogate, Sreenidhi Nair, Raman Bahal, Theodore P Rasmussen, Jose E. Manautou and Xiao-bo Zhong
Drug Metabolism and Disposition February 27, 2022, DMD-MR-2021-000417; DOI: https://doi.org/10.1124/dmd.121.000417

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ADME of FDA-approved ASO drugs

Julia M Migliorati, Sunna Liu, Anna Liu, Anagha Gogate, Sreenidhi Nair, Raman Bahal, Theodore P Rasmussen, Jose E. Manautou and Xiao-bo Zhong
Drug Metabolism and Disposition February 27, 2022, DMD-MR-2021-000417; DOI: https://doi.org/10.1124/dmd.121.000417
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