DRUG DISCOVERY INTERFACEEstimating Unbound Volume of Distribution and Tissue Binding by In Vitro HPLC-Based Human Serum Albumin and Immobilised Artificial Membrane-Binding Measurements
Section snippets
INTRODUCTION
Early drug discovery efforts usually concentrate on finding compounds with high affinity to the target. High potency is usually the key selection criterion of compound progression. However, highly potent compounds tend to be more lipophilic and large and do not have the desired pharmaco-kinetic, absorption, distribution and toxicity profiles.1., 2., 3. Taking into account not only the potency but also the in vivo distribution profile and the underlying physico-chemical properties earlier in the
EXPERIMENTAL
The investigated compounds were either known drug molecules obtained from commercial sources or in-house project compounds; all of them passed the in-house liquid chromatography--mass spectrometry (LC--MS) quality control test (purity ≥80%). The principles and method validation of the chromatographic determination of the lipophilicity of compounds and binding to serum albumin, IAM, are described in detail in our earlier publications.12,17., 18., 19. Here, we give a short description of the
RESULTS AND DISCUSSION
Tables 4 and 5 summarise the measured serum albumin binding (log KHSA) the IAM binding (log KIAM) and the acid/character determined from the CHI log D values measured at three different pHs for the training and test sets of known drug molecules, respectively. To establish the relative contribution of the albumin and phospholipid binding with the increase in the unbound volume of distribution, multiple regression analysis was performed.
Equations 7 and 8 were obtained for the correlation between
CONCLUSIONS
We have described an HPLC methodology based on retention time measurements by using biomimetic immobilised HSA and IAM. The measured albumin and phospholipid binding data could be used to derive equations for the estimation of in vivo unbound volume of distribution (Vdu) of known drug molecules in human. It was found that the sum of albumin and phospholipid binding is proportional to the Vdu. It was also demonstrated that the fraction unbound in tissues (fut) is inversely related to the unbound
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