The in vivo unbound volume of distribution (V(du)) 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 V(du) 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).
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