EVALUATION OF THE MASS BALANCE ASSUMPTION WITH RESPECT TO THE 2-RESISTANCE MODEL OF INTESTINAL-ABSORPTION BY USING INSITU SINGLE-PASS INTESTINAL PERFUSION OF THEOPHYLLINE IN RATS

Methods of analyzing drug absorption data from rat intestinal-perfusion experiments are discussed in terms of mass-transfer resistances, or reciprocal permeabilities, and mass balances. Typically, a two-resistance model is used to determine the dimensionless effective permeability (P(eff)) by measuring the disappearance of drug from the perfusing solution. Unstated assumptions in two-resistance models are (1) the portal blood is under sink conditions and (2) complete transfer of drug occurs from the intestinal perfusate to the portal vein. The assumption of sink conditions is generally acceptable, because the drug concentration in portal blood is approximately two orders of magnitude less than in the perfusate. Single-pass intestinal-perfusion experiments were performed on rats with theophylline as a model compound. The drug mass leaving the intestinal perfusate was substantially less than the drug mass appearing in the portal plasma; that is, the assumption of complete transfer did not hold for theophylline in this experimental system. These data indicate that models based on the two-resistance theory can lead to overestimation of P(eff) by the ratio of the drug mass leaving the perfusate to the drug mass appearing in the plasma. For compounds for which the assumption of complete transfer does not hold, a more accurate estimate of P(eff) may be determined by dividing the value derived from perfusate data by the mass balance ratio (i.e., the drug mass leaving the perfusate divided by the drug mass appearing in the plasma).