Aqueous solubility high permeability

The applicability of PBPK models can be described in the context of the BDDCS classification [24]. PBPK models are very predictive for class 1 and class 2 compounds. However for poorly soluble compounds, the use of aqueous solubility is shown to be inadequate for reliable prediction of oral absorption in physiologically based models [7]. In such cases, it is recommended to use solubility measured in simulated intestinal fluids (FeSSIF, FaSSIF). Such data proved to be very relevant to simulate the oral absorption of BCS 2 (low solubility, high permeability) compounds [25]. 

High solubility-high permeability (e.g. Metoprolol, 1-Dopa) Formulation principles for class I compounds are normally straightforward. Aqueous solutions and in situ suspensions cover the needs for an early formulation. 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

Drugs in Class II have low aqueous solubility (but high membrane permeability), and any factor affecting dissolution rate would be expected to have an impact on the absorption of such compounds. Factors that are noted in Fig. 11, such as fluid pH, volume and viscosity, and bile secretion (especially in response to fatty foods), might be expected to play a role in dissolution rate and thereby affect absorption. Compounds that fall into this class include carbamazepine, cyclosporin, digoxin, griseofulvin, and spironolactone. Food would be expected to exert a potentially significant affect on... 

Aqueous solubility is typically inversely proportional to lypophilicity. Lypophilicity represents the affinity of a molecule (or moiety) for a lypophilic environment. Dmg solubility is also an important attribute to its oral absorption and subsequent permeability through membranes. In medicinal chemistry, solubility for a 1-mg kg dose of 5,50, and 500 p,g mL is estimated to be low, medium, and high, respectively (Van de Waterbeemd, 2002). Solubility characteristics have long been recognized as important in pharmaceutical chemistry and are part and parcel of the drug design process. For example, the solubility can be used to determine the maximal absorbable dose (MAD), that is. 

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