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a The reflection coefficient <7 is defined in the text. The direction of the arrows indicates an increase in permeability. Source: From Refs. 17—19.

Within a homologous series of compounds, the first few small members are readily permeable because of the polar route of membrane penetration. Permeability decreases for the next several members (i.e., s increases), and then increases as the carbon chain length increases. The regular influence of chain length on permeability is a result not of increased solubility in the lipid phase of the membrane but of the unique interaction of hydrocarbon chains with water. The nonpolar hydrocarbon molecules are surrounded by a local region of water that has a more highly ordered structure than bulk water. This "iceberg" structure of water results in increased Ko/w, and membrane permeability as the carbon chain length is increased because of the compound being "pushed out" of the aqueous phase by the resulting gain in entropy.

There has been great interest in developing quantitative, structure=activity relationships to predict drug absorption (19). Such relationships could prove extremely useful in the early stages of drug design and in conjunction with high-throughput screening of hundreds of new molecules during early drug discovery to produce optimum absorption characteristics. Another very practical approach involves "data mining," whereby large databases are examined to characterize the properties of those compounds exhibiting good absorption and, perhaps more importantly, the reason for poor absorption.

On the basis of a review of the physical chemical properties of marketed drugs, Lipinski and coworkers have proposed an empirical "rule of 5" (20). This rule may help pharmaceutical scientists in reaching an early decision about the potential candidacy for further development of a new chemical entity. The rule states that a chemical candidate is likely to display poor absorption or poor membrane permeability if two or more of the following criteria are met (and assuming passive membrane transport):

1. There are more than five hydrogen bond donors.

2. There are more than 10 hydrogen bond acceptors.

3. The molecular weight is greater than 500.

4. Log Ko/w is greater than 5.

pKa and pH

Most drug molecules are either weak acids or bases that will be ionized to an extent determined by the compound's pKa and the pH of the biological fluid in which it is dissolved. The importance of ionization in drug absorption is based on the observation that the nonionized form of the drug has a greater Ko/w than the ionized form and, since Ko/w is a prime determinant of membrane penetration, ionization would be expected to influence absorption. The observation that pH influences the membrane penetration of ionizable drugs is not a recent finding. At the turn of the previous century, Overton was able to relate pH to the rate of penetration of various alkaloids into cells, and he noted the resulting influence in toxicity. Other investigators have made similar observations with respect to the influence of pH on the penetration of alkaloids through the conjunctival and mammalian skin (21). The rate of penetration of these weak bases is enhanced by alkalinization because of a greater fraction of the nonionized species being present. Travell (22) examined the influence of pH on the absorption of several alkaloids from the stomach and intestine of a cat. Following ligation of the proximal and distal ends of the stomach of the anesthetized cat, a 5-mg/kg solution of strychnine at pH 8.5 caused death within 24 minutes; however, the same dose at pH 1.2 produced no toxic response. Identical results were found with nicotine, atropine, and cocaine. The same trend was also seen when the drug solution was instilled into ligated intestinal segments and after oral administration (via stomach tube) to ambulatory animals. These results indicated that

Table 5 Influence of pH on Drug Absorption from the Small Intestine of a Rat

Drug

Percentage absorbed pH 4

pH 5

pH 7

pH 8

Acids 5-Nitrosalicylic acid Salicylic acid Acetylsalicylic acid Benzoic acid Bases Aniline Aminopyrine p-Toluidine Quinine

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