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Lipophilic Conjugates of Drugs: A Tool to Improve Drug Pharmacokinetic and Therapeutic Profiles

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Abstract

Lipophilic conjugates (LCs) of small molecule drugs have been used widely in clinical and pre-clinical studies to achieve a number of pharmacokinetic and therapeutic benefits. For example, lipophilic derivatives of drugs are employed in several long acting injectable products to provide sustained drug exposure for hormone replacement therapy and to treat conditions such as neuropsychiatric diseases. LCs can also be used to modulate drug metabolism, and to enhance drug permeation across membranes, either by increasing lipophilicity to enhance passive diffusion or by increasing protein-mediated active transport. Furthermore, such conjugation strategies have been employed to promote drug association with endogenous macromolecular carriers (e.g. albumin and lipoproteins), and this in turn results in altered drug distribution and pharmacokinetic profiles, where the changes can be ‘general’ (e.g. prolonged plasma half-life) or ‘specific’ (e.g. enhanced delivery to specific tissues in parallel with the macromolecular carriers). Another utility of LCs is to enhance the encapsulation of drugs within engineered nanoscale drug delivery systems, in order to best take advantage of the targeting and pharmacokinetic benefits of nanomedicines. The current review provides a summary of the mechanisms by which lipophilic conjugates, including in combination with delivery vehicles, can be used to control drug delivery, distribution and therapeutic profiles. The article is structured into sections which highlight a specific benefit of LCs and then demonstrate this benefit with case studies. The review attempts to provide a toolbox to assist researchers to design and optimise drug candidates, including consideration of drug-formulation compatibility.

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Authors and Affiliations

  1. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia

    Sifei Han, Chris Porter & Natalie Trevaskis

  2. Suzhou Institute of Drug Innovation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Suzhou, Jiangsu, 215123, China

    Sifei Han & Lianghe Mei

  3. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia

    Tim Quach

  4. PureTech Health, 6 Tide Street, Boston, MA, 02210, USA

    Tim Quach

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Han, S., Mei, L., Quach, T. et al. Lipophilic Conjugates of Drugs: A Tool to Improve Drug Pharmacokinetic and Therapeutic Profiles. Pharm Res 38, 1497–1518 (2021). https://doi.org/10.1007/s11095-021-03093-x

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