Estimation of volume of distribution in humans from high throughput HPLC-based measurements of human serum albumin binding and immobilized artificial membrane partitioning

F. Hollósy, Klára Valkó, Anne Hersey, Shenaz Nunhuck, G. Kéri, Chris Bevan

Research output: Article

64 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6958-6971
Number of pages14
JournalJournal of Medicinal Chemistry
Volume49
Issue number24
DOIs
Publication statusPublished - nov. 30 2006

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Artificial Membranes
Serum Albumin
High Pressure Liquid Chromatography
Throughput
Membranes
Biomimetics
Molecules
Acids
Pharmaceutical Preparations
Drug Discovery
Blood Proteins
Phospholipids
Protein Binding
Membrane Proteins

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

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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.",
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year = "2006",
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T1 - Estimation of volume of distribution in humans from high throughput HPLC-based measurements of human serum albumin binding and immobilized artificial membrane partitioning

AU - Hollósy, F.

AU - Valkó, Klára

AU - Hersey, Anne

AU - Nunhuck, Shenaz

AU - Kéri, G.

AU - Bevan, Chris

PY - 2006/11/30

Y1 - 2006/11/30

N2 - 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.

AB - 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.

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