title: Estimation of volume of distribution in humans from high throughput HPLC-based measurements of human serum albumin binding and immobilized artificial membrane partitioning.
abstract: 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 K (IAM)) and the plasma protein binding (log K (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 K (IAM)-0.22 log K (HSA)-0.66; n=179, r2=0.76, s=0.33, and F=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.
authors.affiliation: Computational, Analytical and Structural Sciences, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY United Kingdom.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Hollósy
authors.forename: Klara
authors.initials: K
authors.lastname: Valkó
authors.forename: Anne
authors.initials: A
authors.lastname: Hersey
authors.forename: Shenaz
authors.initials: S
authors.lastname: Nunhuck
authors.forename: György
authors.initials: G
authors.lastname: Kéri
authors.forename: Chris
authors.initials: C
authors.lastname: Bevan
mesh_terms: D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D003627:Data Interpretation, Statistical; D006801:Humans; D008567:Membranes, Artificial; D008954:Models, Biological; D018716:Molecular Mimicry; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D010599:Pharmacokinetics; D010743:Phospholipids / Q000737:chemistry; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry*
chemical_list: D008567:Membranes, Artificial; D004364:Pharmaceutical Preparations; D010743:Phospholipids; D012709:Serum Albumin