Elucidation of the role of hydrophobic bonding in influencing intestinal absorption of model sulfonamides and revealing possible mechanism of drug absorption in rat model.
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 degrees C. The absorption rate constant (Kab) of each sulfonamide increased with increase in temperature and, at each temperature, Kab was the highest for sulfamethazine and the lowest for sulfadiazine. Applying the activated complex formation theory, the energy of activation (Ea), free energy of activation (delta F*), enthalpy of activation (delta H*), and entropy of activation (delta S*) of absorption were determined for the sulfonamides to gain some insight into the mechanism of their intestinal absorption. The high values of delta F* indicated that the barrier for sulfonamide absorption was great. For each drug, the value of delta H* was positive and that the delta S* negative. However, delta H* and delta S* were the highest for sulfamethazine and the lowest for sulfadiazine, thus revealing the influence of hydrophobic bonding in increasing Kab 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.
Chow
S L
SL
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, MI 48202.
Nagwekar
J B
JB
D000818:Animals; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D007408:Intestinal Absorption / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013411:Sulfadiazine / Q000378:metabolism / Q000493:pharmacokinetics; D013416:Sulfamerazine / Q000378:metabolism / Q000493:pharmacokinetics; D013418:Sulfamethazine / Q000378:metabolism / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000378:metabolism / Q000493:pharmacokinetics*; D013696:Temperature; D013816:Thermodynamics
D013449:Sulfonamides; D013411:Sulfadiazine; D013418:Sulfamethazine; D013416:Sulfamerazine