Partition coefficient oral bioavailability

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

The genesis of in silico oral bioavailability predictions can be traced back to Lip-inski s Rule of Five and others qualitative attempts to describe drug-like molecules [13-15]. These processes are useful primarily as a qualitative tool in the early stage library design and in the candidate selection. Despite its large number of falsepositive results, Lipinski s Rule of Five has come into wide use as a qualitative tool to help the chemist design bioavailable compounds. It was concluded that compounds are most likely to have poor absorption when the molecular weight is >500, the calculated octan-l-ol/water partition coefficient (c log P) is >5, the number of H-bond donors is >5, and the number of H-bond acceptors is >10. Computation of these properties is now available as an ADME (absorption, distribution, metabolism, excretion) screen in commercial software such as Tsar (from Accelrys). The rule-of-5 should be seen as a qualitative, rather than quantitative, predictor of absorption and permeability [16, 17]. 

In recent years there has been an increased interest in the utility of lipid-based delivery systems to enhance oral bioavailability (4). It is generally known that membrane permeability is directly correlated to a drug s water-lipid partition coefficient however, the systemic availability of highly lipophilic drugs is impeded by their low aqueous solubility. In an effort to improve this solubility-limited bio-availabiliy,formulators have turned to the use of lipid excipients to solubilize the compounds before oral administration. Several formulations are currently on the market, for example, Sandimmun/Neoral (cyclosporin microemulsion), Norvir (ritonavir), and Fortovase (saquinavir)... 

Lipophilicity is another molecular characteristic of a compound that often dictates biological properties including the compound oral bioavailability, tissue distribution, cellular uptake, receptor binding, metabolism, and excretion. The most commonly used measure of lipophilicity is the logarithm of the 1-octanol/water partition coefficient (log Hence, computational... 

Lipophilicity is often expressed as log P, the logarithm of the partition coefficient of a compound between octanol and water. A distribution coefficient (log D) is also used to quantify lipophilicity in the event that charge states need to be taken into consideration. A log D value is the logarithm of the coefficient of the distribution of a molecule between water and octanol at a particular pH, typically 7.4 because of physiological relevance. Based on an analysis of the physical properties of orally bioavailable drags, the optimal log P for an orally administered drag is between 1 and 5 [122]. 

---