Estimation of Volume of Distribution in Humans from High Throughput HPLC-Based
Measurements of Human Serum Albumin Binding and Immobilized Artificial Membrane
Partitioning
Ferenc Hollósy
Klára Valkó
Anne Hersey
Shenaz Nunhuck
György Kéri
Chris Bevan
10.1021/jm050957i.s002
https://acs.figshare.com/articles/journal_contribution/Estimation_of_Volume_of_Distribution_in_Humans_from_High_Throughput_HPLC_Based_Measurements_of_Human_Serum_Albumin_Binding_and_Immobilized_Artificial_Membrane_Partitioning/3044179
The volume of distribution (VD) in humans of 179 known drug molecules (acids, bases, and neutrals) has
been modeled using two biomimetic-binding measurements. The phospholipid binding (log <i>K</i> (IAM)) and
the plasma protein binding (log <i>K</i> (HSA)) have been calculated from gradient HPLC retention times on
immobilized artificial membrane (IAM) and on human serum albumin (HSA) columns, respectively. The
log VD values showed good correlation with the compounds' relative binding to IAM and HSA as follows:
log VD = 0.44 log <i>K</i> (IAM) − 0.22 log <i>K</i> (HSA) − 0.66; <i>n</i> = 179, <i>r</i><sup>2</sup> = 0.76, <i>s</i> = 0.33, and <i>F</i> = 272. It
was also observed that positively charged molecules bind relatively more to IAM, while negatively charged
ones bind more to HSA, in line with the empirical observation that bases tend to have a larger volume of
distribution than acids. These results suggest that with the help of these two simple high throughput HPLC-based biomimetic binding measurements an important in vivo drug disposition property can be estimated
for use in early drug discovery.
2006-11-30 00:00:00
log VD values
plasma protein binding
HSA
IAM
Membrane PartitioningThe volume
Human Serum Albumin Binding
vivo drug disposition property
log K
gradient HPLC retention times
0.44 log K