ANALYSIS OF INTESTINAL PERFUSION DATA FOR HIGHLY PERMEABLE DRUGS USING A NUMERICAL AQUEOUS RESISTANCE-NONLINEAR REGRESSION METHOD

Purpose. To develop, validate and apply a method for analyzing the int estinal perfusion data of highly permeable compounds using the Numeric al Aqueous Resistance (NAR) theory and nonlinear regression (NAR-NLR) and to compare the results with the well-established Modified Boundary Layer (MEL) Analysis. Methods. The NAR-NLR method was validated and t he results were compared to the MBL analysis results using previously reported cephradine jejunal perfusion data. Using the Single Pass Inte stinal Perfusion (SPIP) method, the concentration dependence of intest inal permeability was investigated for formycin B, proline, and thymid ine, three compounds reported to be absorbed by carrier-mediated trans port processes. The MBL and NAR-NLR analyses were then applied to the three sets of SPIP data. Results. The results demonstrate that the int rinsic MBL transport parameters were highly variable and, in one case, the analyses failed to give a statistically significant Michaelis con stant. The MBL mean dimensionless wall permeabilities (P(w)) were gre ater than the NAR-NLR P(w) and were also highly variable. In all case s, the NAR-NLR variability was significantly lower than the MBL variab ility. The extreme variability in the MEL-calculated P(w) is due to t he sensitivity of P(w) when the fraction of unabsorbed drug (C-m/C-o) is low or, alternatively, when P(w) approached the aqueous permeabil ity, P(aq). Conclusion. The NAR-NLR method facilitates the analysis o f intestinal perfusion data for highly permeable compounds such as tho se absorbed by carrier-mediated processes at concentrations below thei r K-m. The method also allows for the use of a wider range of flow con ditions than the MBL analysis resulting in more reliable and less vari able estimates of intestinal transport parameters as well as intestina l wall permeabilities.