Surfactant Interactions with Biomembranes and Drug Absorption

This article summarises work which has been carried 5ü€ at Strathclyde and elsewhere on the mechanisms of the effect of nonionic surfactants on drug absorption. Experiments carried out in whole animals are often difficult to interpret unless treatment is confined to a small or localised part of the animal e.g. the rectal cavity, because of dilution of the surfactantdrug system and possible interactions of components of the formulation with naturally occurring materials. Resort to simple animal models is essential if surfactant structure-activity relationships are to be obtained. Experiments on drug transport across the gill membrane of the goldfish, Carassius auratus and the isolated rabbit gastric mucosa are discussed in relation to the factors influencing increases in drug penetration. Concentration—dependent effects are discussed and some recent results on enhanced high dose methotrexate absorption in mice are discussed. Consideration is given to the biological effects of surfactants which can influence drug absorption from the gastro-intestinal tract of animals and human subjects and to the possibility that surfactants may be used deliberately not only to enhance drug absorption, but also to secure penetration into specialised tissues. Drugs are almost never administered as such to the body, but as formulations containing many ingredients presumed to be inert. Surfactants used as emulsifying agents, solubilizers, suspensions stabilizers or as wetting agents in formulations can not be considered to be inert additives as they can lead to significant changes inthe biological activity of the active agents in the formulation. Utilisation of a drug involves its release from the formulation, its solution in the body fluids, and its passage through barrier membranes into the systemic blood stream before transport into tissues and eventual arrival at the target organ. Release of poorly soluble drugs from tablets and capsules for oral use may be increased by the presence of surfactants, which may decrease the aggregation of the drug particles and therefore increase the area of particle available for dissolution. The lowering of surface tension may also be a factor in aiding the penetration of water into the drug mass; this wetting effect is operative at low concentrations. Above the critical micelle concentration (CMC) the increase in the saturation solubility of the drug substance by solubilisation in the surfactant micelles can result in more rapid rates of drug solution. Where dissolution is the rate—limiting step in the absorption process, as it is with many poorly soluble drugs, an increase in rate of solution will increase the rate of drug entry into the blood and may affect peak blood levels. Very high concentrations of surfactant in excess of that required to solubilize the drug can decrease drug absorbption by decreasing the chemical potential of the drug. The various sites at which surfactants may influence absorption are depicted in Fig.l. Some surfactants have a direct physiological activity of their own and in the intact animal can thus affect the physiological environment e.g. by altering gastric residence time such that without physico-chemical intervention, a surfactant effect may be seen. It is only possible to isolate some of these effects and to examine the effect of surfactants in each. Studies in whole animals have sometimes given what appear to be contradictory results.