Kinetic modeling of triamterene intestinal absorption and its inhibition by folic acid and methotrexate.

Abstract

The aim of this work was to study the intestinal absorption process of triamterene in situ in rats in order to gain insight on its absorption mechanism. The study shows an example of application of a pharmacokinetic model for drug disappearance from a compartment by simultaneous first order and Michaelis-Menten processes to the intestinal drug disappearance by absorption in a non-steady state system. The parameter used to quantify absorption was the absorption rate constant, determined in situ by means of a loop perfusion technique, performed in colon and in whole small intestine of rat at three pHs (5.00, 7.00 and 8.00) and in the presence of folic acid and methotrexate. Different concentrations of the drug were perfused in each condition. The concentrations versus time data were modeled with different kinetic absorption and inhibition differential equations to obtain the passive and active transport components and to elucidate the inhibition mechanisms. The results obtained confirm that triamterene is absorbed by means of passive diffusion and by a transporter or transporters related to folates. Folic acid and methotrexate are able to inhibit triamterene absorption. The results do not allow the selection of a competitive or non-competitive model for inhibition and this fact could be due to the presence of different carriers. The possibility of the existence of a secretion process sensitive to verapamil is also discussed.