Mathematical and Experimental Validation of Flux Dialysis Method: An Improved Approach to Measure Unbound Fraction for Compounds with High Protein Binding and Other Challenging Properties
Mathematical and Experimental Validation of Flux Dialysis Method: An Improved Approach to Measure Unbound Fraction for Compounds with High Protein Binding and Other Challenging Properties
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DOI：
10.1124/dmd.117.078915
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发表时间：
2018-04-01
影响因子：
3.9
通讯作者：
Fischer, Volker
中科院分区：
文献类型：
--
作者：
Kalvass, J. Cory;Phipps, Colin;Fischer, Volker
测试和验证了一种用于测量具有高蛋白结合力和其他挑战性性质的化合物的游离分数(f(U))的助熔剂透析法。这种方法的原理是，化合物通过不计尺寸的透析膜的初始通量与化合物初始浓度f(U)和非结合透析膜透过率(P-mem)的乘积成正比。因此，在膜P-mem已知的情况下，f(U)可以由初始浓度和通量确定。通过透析含有化合物的人体血浆(供体侧)和不含化合物的血浆(接收方)，并测量化合物进入接收方的比率，确定了14种化合物的复合初始通量。11个化合物已知从传统方法获得的f(U)值(范围为0.000013-0.22)；3个化合物(贝达奎林、拉帕替尼和匹布列韦)先前已限定f(U)值(例如，
A flux dialysis method to measure unbound fraction (f(u)) of compounds with high protein binding and other challenging properties was tested and validated. This method is based on the principle that the initial flux rate of a compound through a size-excluding dialysis membrane is proportional to the product of the compound initial concentration, f(u), and unbound dialysis membrane permeability (P-mem). Therefore, f(u) can be determined from the initial concentration and flux rate, assuming membrane P-mem is known. Compound initial flux rates for 14 compounds were determined by dialyzing human plasma containing compound (donor side) versus compound-free plasma (receiver side) and measuring the rate of compound appearance into the receiver side. Eleven compounds had known f(u) values obtained from conventional methods (ranging from 0.000013 to 0.22); three compounds (bedaquiline, lapatinib, and pibrentasvir) had previously qualified f(u) values (e.g.,