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.

小分子药物的亲脂偶联物 (LC) 已广泛用于临床和临床前研究，以实现许多药代动力学和治疗益处。例如，药物的亲脂性衍生物被用于几种长效注射产品中，为激素替代疗法和治疗神经精神疾病等疾病提供持续的药物暴露。LC 还可用于调节药物代谢，并通过增加亲脂性以增强被动扩散或通过增加蛋白质介导的主动转运来增强药物跨膜渗透。此外，这种偶联策略已被用于促进药物与内源性大分子载体（例如白蛋白和脂蛋白）的结合，这反过来导致药物分布和药代动力学曲线的改变，其中的变化可以是“一般的”（例如延长血浆半衰期）或“特异性的”（例如与大分子载体平行地向特定组织的递送增强）。LC 的另一个用途是增强药物在工程纳米级药物递送系统中的封装，以便最好地利用纳米药物的靶向性和药代动力学优势。目前的综述总结了亲脂性偶联物（包括与递送载体​​组合）可用于控制药物递送、分布和治疗概况的机制。本文分为几个部分，重点介绍 LC 的特定优势，然后通过案例研究证明这一优势。