Elucidation of the role of hydrophobic bonding in influencing intestinal absorption of model sulfonamides and revealing possible mechanism of drug absorption in rat model

Abstract

A recirculation technique was used to study the first-order kinetics of intestinal absorption of un-ionized sulfadiazine, sulfamerazine, and sulfamethazine in rats in situ at 32, 35, and 38 °C. The absorption rate constant (K_ab) of each sulfonamide increased with increase in temperature and, at each temperature, K_ab was the highest for sulfamethazine and the lowest for sulfadiazine. Applying the activated complex formation theory, the energy of activation (E_a), free energy of activation (ΔF*), enthalpy of activation (ΔH*), and entropy of activation (ΔS*) of absorption were determined for the sulfonamides to gain some insight into the mechanism of their intestinal absorption. The high values of ΔF* indicated that the barrier for sulfonamide absorption was great. For each drug, the value of ΔH* was positive and that of ΔS* negative. However, ΔH* and ΔS* were the highest for sulfamethazine and the lowest for sulfadiazine, thus revealing the influence of hydrophobic bonding in increasing K_ab of the sulfonamides with the increase in methyl group content of their molecules. By considering the facts that (1) the microvillus membrane of the intestinal absorptive cells regulates the rate of passive absorption of drugs, (2) the microvillus membrane is rich in proteins, which are located external to the membrane and exposed to the intestinal fluid, and (3) hydrophobic bonding contributes to the activation parameters of absorption, it was postulated that the activated complex formed in the absorption process consisted of a transient association of the sulfonamide molecules with some protein component of the microvillus membrane.