Lipophilic drugs disposition

Takino, T., Nagahama, E., Sakaeda (nee Kakutani),T., Yamashita, F.,Takakura, Y., and Hashida, M. (1995), Pharmacokinetic disposition analysis of lipophilic drugs injected with various lipid carriers in the single-pass rat liver perfusion system, Int. J. Pharm., 114,43 54. 

Many drugs have been recognized to cross the intestinal epithelial cells via passive diffusion, thus their lipophilicity has been considered important. However, as described above, recent studies have demonstrated that a number of drug transporters including uptake and efflux systems determine the membrane transport process. In this chapter, we provide an overview of the basic characteristics of major drug transporters responsible not only for absorption but also for disposition and excretion in order to delineate the impact of drug transport proteins on pharmacokinetics. 

The consequences of intestinal lymphatic transport are therefore more wide ranging than the opportunity to target the intestinal and central lymph and to avoid first-pass metabolism. Indeed, drug transport by means of the intestinal lymph may markedly alter the patterns of subsequent systemic drug clearance and disposition, and these profound alterations could be stimulated simply by a change in formulation. Importantly, the common approach of the use of plasma AUC as an indicator of the available fraction may be misplaced when dealing with lipophilic and lymphotropic drug molecules. 

The relationship between chemical structure, lipophilicity, and its disposition in vivo has been extensively studied. These include solubility, absorption potential, membrane permeability, plasma protein binding, volume of distribution, and renal and hepatic clearance. Activities used in quantitative structure-activity relationships (QSAR) include chemical measurements and biological assays. QSAR currently are applied in many disciplines, with many pertaining to drug design and environmental risk assessment. 

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