Novartis Institutes for Biomedical Research: Horsham, West Sussex, United Kingdom (D.A.S., C.P., P.W., S.J.C.), Cambridge, Massachusetts (J.R.), and Basel, Switzerland (R.A.F.).
Mol Pharmacol. 2014 Apr;85(4):608-17. doi: 10.1124/mol.113.090209. Epub 2014 Jan 29.
Current pharmacological models for determining affinity and kinetics of drugs for membrane receptors assume the interacting molecules are homogeneously distributed in the bulk aqueous phase. The phospholipid membrane can, however, provide a second compartment into which drugs can partition, particularly lipophilic/basic compounds. In this study we measured the phospholipid affinity and receptor binding kinetics of several clinically relevant β2-adrenoceptor agonists and antagonists and demonstrated that the degree of phospholipid interaction directly affects the observed kinetic association rate (k on) and dissociation constant (Kd), but not the dissociation rate (k off) from the target, by concentrating drug in the local environment around the receptor. When the local drug concentration was accounted for, the k on was comparable across the cohort and the corrected Kd was directly related to the k off. In conclusion, we propose a new approach to determining the pharmacology of drugs for membrane targets that accounts for differences in local drug concentration brought about by direct affinity for phospholipids, establishing "micro-pharmacokinetic/pharmacodynamic relationships" for drugs.
目前用于确定药物与膜受体亲和力和动力学的药理学模型假设相互作用的分子在主体水相中均匀分布。然而，磷脂膜可以提供第二个隔室，药物可以分配到其中，特别是亲脂性/碱性化合物。在这项研究中，我们测量了几种临床相关的β2-肾上腺素能受体激动剂和拮抗剂的磷脂亲和力和受体结合动力学，并证明磷脂相互作用的程度直接影响观察到的动力学缔合速率（kon）和解离常数（kd），但不会影响从靶点的解离速率（koff），通过将药物集中在受体周围的局部环境中。当考虑到局部药物浓度时，整个队列的 kon 具有可比性，校正后的 kd 与 koff 直接相关。总之，我们提出了一种新的方法来确定膜靶标药物的药理学，该方法考虑了直接与磷脂亲和力相关的局部药物浓度差异，为药物建立了“微观药代动力学/药效学关系”。
