EFFECT OF COMPLEX FORMATION ON DRUG ABSORPTION .9. DETERMINATION OF INTESTINAL TRANSFER RATE CONSTANT OF SALICYLAMIDE-CAFFEINE COMPLEX

A model describing the overall transfer of a drug across biologic membranes in the presence of a complexing agent is presented. This model has been applied to the transfer of salicylamide across the cannulated everted intestine of the rat in the presence of caffeine. Assuming that (a) salicylamide and the salicylamide‐caffeine complex are transferred at a rate proportional to their respective concentration gradient, and (b) the complex is not dissociated at the surface of the absorbing membrane, it is shown that Kapp./Ksam. = Kcmoplex/Ksam. + Ff (1 — Kcomplex/Ksam.), where Kapp., Ksam., and Kcomplex are intestinal transfer rate constants for salicylamide in the presence of caffeine, for salicylamide alone, and for the salicylamide‐caffeine complex, respectively, and Ff is the fraction of total salicylamide which is not complexed. Since Ff is determined on the basis of an independently obtained stability constant (Ks) of the complex, an adequate fit of the intestinal transfer rate data to the model can be obtained only if the Ks at the transfer rate‐limiting barrier of the intestine does not differ appreciably from that determined in the bulk solution. A plot of Kapp./ Ksam. versus Ff was linear, consistent with the model and the assumptions upon which it is based. The intestinal transfer rate constant of the salicylamide‐caffeine complex was found to be considerably lower than that of salicylamide, but essentially the same as that of caffeine. Copyright © 1969 Wiley‐Liss, Inc., A Wiley Company