Absorption of Drugs Through the Oral Mucosa. III. Fat-Water Solubility Coefficient of Alkaloids

Abstract

It has been shown that the absorption of drugs from the mouth is strictly a selective process. 1 , 2 With even a closely related group of drugs, such as the common alkaloids, marked differences are exhibited by the individual members. Apomorphine, for instance, can be effectively administered by simple sublingual application, whereas morphine is very poorly absorbed. The diacetyl derivative of morphine is absorbed fairly well, whereas the monomethyl derivative is absorbed very poorly. Since all 4 of these drugs are closely related both chemically and pharmacologically, the explanation for this phenomenon of selectivity might reasonably be expected to depend on physical differences. The most prominent suggestion is that of a correlation with the oil-water distribution coefficient. This relationship has been extensively developed for other problems of cell permeability, 3 , 4 and also has been described as being the decisive factor in absorption through the oral mucosa. 5 However, for this latter aspect of the correlation, the only previous demonstration of the principle is the fact that glycerol trinitrate is readily soluble in oils and only sparingly soluble in water. The present report presents a study of this relationship for a series of common drugs which have more limited oil solubilities.

In Table I the ratio of sublingual doses to similarly effective subcutaneous doses is compared with the fat-water solubility coefficient of the same drug. The sublingual/subcutaneous ratios, which have been previously described 1 , 2 are not to be considered as natural constants in the same sense as solubility figures, but simply as approximate expressions of their absorption behavior. The oil-water solubility coefficients are usually considered equivalent to the distribution ratios of the same drugs in a 2-phase system made up of equal volumes of oil and water. 6 All the figures for oil solubility and one of those for water solubility (dilaudid) were determined for the purposes of this correlation.