Mahar Doan Kelly M, Humphreys Joan E, Webster Lindsey O, Wring Stephen A, Shampine Larry J, Serabjit-Singh Cosette J, Adkison Kimberly K, Polli Joseph W
Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.
J Pharmacol Exp Ther. 2002 Dec;303(3):1029-37. doi: 10.1124/jpet.102.039255.
Membrane permeability and P-glycoprotein (Pgp) can be limiting factors for blood-brain barrier penetration. The objectives of this study were to determine whether there are differences in the in vitro permeability, Pgp substrate profiles, and physicochemical properties of drugs for central nervous system (CNS) and non-CNS indications, and whether these differences are useful criteria in selecting compounds for drug development. Apparent permeability (P(app)) and Pgp substrate profiles for 93 CNS (n = 48) and non-CNS (n = 45) drugs were determined by monolayer efflux. Calcein-AM inhibition assays were used to supplement the efflux results. The CNS set (2 of 48, 4.2%) had a 7-fold lower incidence of passive permeability values <150 nm/s compared with the non-CNS set (13 of 45, 28.9%). The majority of drugs (72.0%, 67 of 93) were not Pgp substrates; however, 49.5% (46 of 93) were positive in the calcein-AM assay when tested at 100 microM. The CNS drug set (n = 7 of 48, 14.6%) had a 3-fold lower incidence of Pgp-mediated efflux than the non-CNS drug set (n = 19 of 45, 42.2%). Analysis of 18 physicochemical properties revealed that the CNS drug set had fewer hydrogen bond donors, fewer positive charges, greater lipophilicity, lower polar surface area, and reduced flexibility compared with the non-CNS group (p < 0.05), properties that enhance membrane permeability. This study on a large, diverse set of marketed compounds clearly demonstrates that permeability, Pgp-mediated efflux, and certain physicochemical properties are factors that differentiate CNS and non-CNS drugs. For CNS delivery, a drug should ideally have an in vitro passive permeability >150 nm/s and not be a good (B --> A/A --> B ratio <2.5) Pgp substrate.
膜通透性和P-糖蛋白（Pgp）可能是血脑屏障穿透的限制因素。本研究的目的是确定用于中枢神经系统（CNS）和非CNS适应症的药物在体外通透性、Pgp底物谱和理化性质方面是否存在差异，以及这些差异是否是药物开发中选择化合物的有用标准。通过单层外排测定了93种CNS药物（n = 48）和非CNS药物（n = 45）的表观通透性（P(app)）和Pgp底物谱。使用钙黄绿素-AM抑制试验来补充外排结果。与非CNS组（45种中的13种，28.9%）相比，CNS组（48种中的2种，4.2%）被动通透性值<150 nm/s的发生率低7倍。大多数药物（93种中的67种，72.0%）不是Pgp底物；然而，在100 microM测试时，49.5%（93种中的46种）在钙黄绿素-AM试验中呈阳性。CNS药物组（48种中的7种，14.6%）的Pgp介导的外排发生率比非CNS药物组（45种中的19种，42.2%）低3倍。对18种理化性质的分析表明，与非CNS组相比，CNS药物组具有更少的氢键供体、更少的正电荷、更大的亲脂性、更低的极性表面积和更低的柔性（p < 0.05），这些性质可增强膜通透性。这项对大量不同上市化合物的研究清楚地表明，通透性、Pgp介导的外排和某些理化性质是区分CNS和非CNS药物的因素。对于CNS给药，理想情况下，药物的体外被动通透性应>150 nm/s，且不是良好的（B→A/A→B比值<2.5）Pgp底物。
