DRUG DISCOVERY INTERFACE
Estimating Unbound Volume of Distribution and Tissue Binding by In Vitro HPLC-Based Human Serum Albumin and Immobilised Artificial Membrane-Binding Measurements

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ABSTRACT

The in vivo unbound volume of distribution (Vdu) can be used to estimate the free steady-state plasma concentration with a given dose of a drug administered intravenously. We have demonstrated that the calibrated HPLC retention times obtained on biomimetic stationary phases, such as immobilised human serum albumin and phosphatidyl-choline, can be used to estimate compounds' in vivo behaviour. The mechanistic models are based on the assumption that the sum of the albumin and phospholipid binding has the most significant impact on reducing compounds' free concentration both in plasma and in tissues. The model equations were obtained using the literature human volume of distribution and fraction unbound in plasma values of 135 known drug molecules and have been tested on a further 300 in-house compounds. The model can be used to design compounds with low Vdu values and high fraction unbound in tissues which will minimise the required dose to achieve the efficacious free concentration at the target organ (excluding possible active transport processes).

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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      Citation Excerpt :

      In this case, the maximum drug efficiency (DEmax) can be considered as the reciprocal value of the Vdu. Fig. 13.36 shows the agreement between the in vivo DEmax values and the estimated values using the model for Vdu described by Eq. (13.44) and taking the reciprocal value of the estimated Vdu values [188]. It can be seen that for many therapeutic areas, the in vivo drug efficiency max could be modelled by the in vitro drug efficiency max within a 1 log unit error.

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