Permeability Absorption Models 531 Physicochemical Methods

For orally administered compounds, the systemic exposure depends on many different factors. In general, physicochemical properties such as molecular weight, pKa, lipophilicity, charge/ionization, solubility, gastrointestinal pH and molecular size are the major determinants of intestinal permeability. Aqueous solubility of the compound in the intestinal tract is also an important factor that dictates the dissolution characteristics of the compound eventually influencing the oral bioavailability. Physicochemical methods are attractive because of their high-throughput capacity, efficiency and reproducibility to predict passive diffusion. However, these models often lead to inaccurate prediction because of the lack of real physiological conditions that govern membrane permeability/absorption in vivo.

5.3.1.1 Lipophilicity (Log P/Log D)

As a measure of drug-membrane interaction, lipophilicity is one of the most important physicochemical parameters in predicting and interpreting membrane permeability (Ho et al., 1977). In most of the early studies (Schanker et al., 1958; Houston et al., 1974; Dressman et al., 1985), the oral drug absorption was demonstrated to be dependent on the lipophilicity. Historically, the octanol-water partition coefficient (Log P) was accepted as a surrogate to biological systems for predicting absorption. But now it is widely recognized that use of Log P alone for predicting absorption is an over simplification of a complex process and often leads to inaccurate estimation. The transcellular diffusion of compounds from the luminal to serosal side in the intestinal epithelia involves the partitioning of the drug from the aqueous luminal region to nonpolar lipid bilayers of the cell membrane followed by the partitioning out from the lipid layers to the aqueous serosal region. Transport across biological membranes is a complex process that includes passive as well as carrier-mediated processes for influx and efflux. Log P values provide indirect information of the extent of passive transcellular transport possible for various drugs. For a structurally related series of compounds in which transport is largely mediated by a passive mechanism, the relationship between permeability and lipophilicity is generally bell shaped. However, for a diverse set of compounds in which parallel transport processes may be occurring in addition to the passive component, the correlation with lipophilicity is normally lacking (Ho etal., 1977).

5.3.1.2 Absorption Potential

Dressman and colleagues (Dressman et al., 1985) proposed a parameter, Absorption Potential (AP), that incorporated the various basic physicochemical parameters in one single equation and was highly predictive of the extent of absorption in humans.

/ [So Vl AP = Log I -PFnon where AP is the absorption potential, P is the octanol-water partition coefficient for the drug, Fnon is the fraction of drug nonionized at pH 6.5, So is the aqueous solubility of nonionized species at 37 °C, Vl is the luminal volume (~250 mL) and Xo is the drug dose. A relatively good correlation was demonstrated between absorption potential vs. fraction absorbed in human subjects. There was a sig-moidal relationship observed between fraction absorbed and absorption potential. However, absorption potential does not account for carrier-mediated transport and thus is limited in its utility for predicting permeabilities only for passively transported compounds.

5.3.1.3 Immobilized Artificial Membrane (IAM)

IAM is a chromatographic surface prepared by covalently immobilizing cell membrane phospholipids to solid surfaces at monolayer density. IAM chro-matography column emulates the lipid environment of cell membranes (Pidgeon 1990a,b). IAM chromatography is experimentally simple and potentially capable of screening a large number of compounds. Pidgeon and colleagues have demonstrated the utility of this methodology as an accurate, cost effective and efficient predictor of permeability of test compounds. The predominant factor that regulates the passage of drugs across the gastrointestinal mucosa is their ability to passage through the lipid cell membranes. Log k' derived from the IAM column showed reasonable correlation to drug partitioning into liposomes and permeability across Caco-2 cell monolayers. Various modifications of IAM have been studied by different investigators (Beigi et al., 1995; Yang et al., 1996; Stewart and Chan, 1998; Krause et al., 1999) and the results obtained have been shown to correlate with other parameters such as: partitioning into liposome membranes, Caco-2 cell permeability and intestinal absorption.

The IAM methodology has been used to predict not only drug intestinal absorption but also solute partitioning into liposomes, brain uptake, and human skin permeability. But, it is important to recognize that lipid composition of various cell membranes in the body differs and is not necessarily consistent even within a given cell type under different conditions. Also, the artificial membranes themselves lack the paracellular pores that form an integral part of a biological membrane architecture and the transporter proteins that are involved in the carrier-mediated transport of drugs. Thus, even though these simplified artificial membranes might be capable of predicting the absorption of a series of compounds that are passively transported across cell membrane, it has severe limitations in screening compounds that are hydrophilic and small in size (candidates for paracellular transport) or predominantly transported by carrier proteins.

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