A

Jmax)

Solubility

Figure 13 This figure illustrates the "mesa" response resulting for the diffusion model. Two plateau functions corresponding to different Mr are shown.

Solubility

Distribution coefficient

Figure 13 This figure illustrates the "mesa" response resulting for the diffusion model. Two plateau functions corresponding to different Mr are shown.

function of solubility and distribution coefficient for two different Mt values. Several features of the model are depicted, and these qualitative, or semiquantitative, aspects presumably encompass the principles of corneal permeation.

Inferred from this model is the relative independence of the effects of solubility and partitioning. For each property there is a characteristic threshold above which the log of the flux increases more slowly than below it, and the value of the threshold for one variable is not very dependent on the value of the other variable. This tabletop perspective has led to the name mesa model. The relative independence signifies that neither property can totally compensate for a deficiency in the other. This is not to say that these properties are independent of one another in a chemical sense, quite the contrary. However, in the hypothetical sense, if one property were varied independently of the other, then the consequences on flux are relatively independent. Clearly, dependence on molecular mass, even for relatively low-molecular-mass agents, can be significant.

Ex vivo studies of transcorneal transport in animal models have been used to establish the characteristics of passive diffusional motion, the conventional means by which drugs reach internal ocular tissues. Although such analysis neglects the complications of tear flow, tear drainage, nonproductive membrane absorption, elimination from the aqueous humor, and so forth, measurements of corneal transport measurements have been important in establishing correlations of model calculations with experimental measurements of transmembrane transport. Modifications (230) of the classical ex vivo experiments of transport across excised, but metabolizing, rabbit corneas (18,24,26,231) have provided information both about targeting of similar molecules from the same pharmacological class (19) and confirmation of the balance of different anatomical pathways for accession (32).

The rough brushstroke agreement between model and experiment is illustrated by the results shown in (Fig. 14), for which the correspondence of theoretical with experimental permeability coefficients for the compounds listed in Table 2 and P-adrenergic blockers studied by Lee (48,232) and Schoenwald (26) are plotted. The calculated values utilized

Calculated vs measured permeability coefficients

Figure 14 Plot of data in Table 2, the theoretically computed permeability coefficient versus that measured. The larger influence on flux is often the range of solubility, which can increase the range in flux by several orders of magnitude.

Calculated vs measured permeability coefficients

K permeas "IE5

Figure 14 Plot of data in Table 2, the theoretically computed permeability coefficient versus that measured. The larger influence on flux is often the range of solubility, which can increase the range in flux by several orders of magnitude.

Table 2 Permeability of ß-Adrenergic Blockers

Compound

Chemical formula

Molecular weight

Distribution coefficient

K^rc x IE5 (cm/sec)

X^f8 X IE5 (cm/sec)

Acebutolol

Ci8H28N204

Was this article helpful?

0 0

Post a comment