Studies on the reliability of a novel absorption-lipophilicity approach to interpret the effects of the synthetic surfactants on drug and xenobiotic absorption.

Some theoretical principles of the absorption/lipophilicity approach, which attempts to explain the effects of the synthetic surfactants on xenobiotic and drug intestinal absorption, are reviewed and experimentally checked by examining the correlations obtained between "in situ" absorption constants, ka, found in rat colon, and "in vitro" lipophilicity indexes, K', for two compound series (secondary aliphatic amines and phenylalkylamines) in the absence and in the presence of the nonionic surfactant Polysorbate 80, in the intestinal perfusion fluid. Evidence is given for the following actions of the synthetic surfactant: at its critical micelle concentration (CMC), it increases the polarity of the absorbing membrane and, at the same time, it disrupts the aqueous stagnant diffusion layer adjacent to the mucosal barrier. When a supramicellar concentration (SMC) is used, the above actions are almost totally masked by the micellar solubilization of the tested amines, which decreases their absorption constants relative to those found at CMC, as markedly as solute lipophilicity increases. As a consequence of these actions, the correlations between ka and K', which are clearly hyperbolic in free solution, become potential in the presence of the surfactant at its CMC, whereas at SMC a bilinear correlation is obtained. Absorption via lipophilic ionized species seems to take place for both compound series. Mathematical and physicochemical interpretations of this behaviour are outlined, and biopharmaceutical implications of these phenomena are discussed.

Absorption mechanisms of secondary aliphatic amines in rat colon and small intestine.

This study is intended to be a further and conclusive validation of the bihyperbolic model equation proposed by Plá-Delfina and Moreno to describe passive intestinal absorption mechanisms through the analysis of absorption-lipophilicity correlations for homologous series of xenobiotics and drugs. Secondary aliphatic amines, largely differing from previously tested substances, were selected as model compounds. Evidence is given which demonstrates that a minimum lipophilicity value exists for absorption in small intestine, instead of a maximum, as probabilistic theories predict. Moreover, bihyperbolic equation provides an excellent fit, with AIC figures up to -29. Aqueous pore absorption was small, presumably due to ionic interactions with pore charges (kp approximately 1.0 h-1), whereas membrane penetration was highly lucrative (km approximately 7.4 h-1), thus indicating that some part of the lipophilic ionic species is capable of penetrating "per se" the lipoidal membrane. As model predicts, bihyperbolic equation collapses to monohyperbolic for colonic absorption, where AIC figures up to -39 were found, with a km value of about 4.0 h-1. Membrane absorption efficiency was, surprisingly, similar in colon and small intestine for the tested solutes; it was attributed to the basic character of the compounds associated with working pH and ion absorption. This latter effect would deserve further investigation in oral sustained-release medication with basic drugs having similar pKa values.

Studies on the reliability of a bihyperbolic functional absorption model. II. Phenylalkylamines.

Evidence is given that demonstrates the reliability of the bihyperbolic equation, proposed by Plá-Delfina and Moreno, in fitting the correlation between absorption rate constants (ka) found in the small intestine and in the colon of the living anesthetized rat, and partition constants (1/RF-1), for a series of phenylalkylamines, a group of compounds which differ largely from others which have been tested. Emphasis is laid on the nonexistence of an optimum of lipophilicity for intestinal absorption/partition correlation: This feature makes inapplicable the probabilistic approaches to the reported data.