GI absorption of beta-lactam antibiotics I: kinetic assessment of competing absorption and degradation in GI tract.

An equation was derived for the simultaneous assessment of rate constatns for absorption and nonenzymatic degradation of unstable drugs in in situ absorption experiments. The equation was substantiated by using a variety of beta-lactam antibiotics in the recirculation technique through the rat small intestine. Plots of the apparent first-order rate constant for the disappearance of the drug from the gut lumen versus the reciprocal of the volume of recirculating solution yielded a straight line with a slope equal to the intrinsic absorption rate constant and with an intercept equal to the nonenzymatic degradation rate constant in the GI lumen. The kinetic method for evaluation of the absorption rate constant also was developed for a more complex situation in the GI lumen involving absorption, nonenzymatic degradation, and enzymatic metabolism. The proposed method was confirmed with carbenicillin indanyl, which was metabolized rapidly to carbenicillin by the action of nonspecific esterase in the intestine. In the absence of information of Michaelis--Menten kinetic parameters, the present method is advantageous for evaluation of the intrinsic absorption rate of all unstable drugs.