Sinko P J, Leesman G D, Waclawski A P, Yu H, Kou J H
College of Pharmacy, Rutgers, State University of New Jersey, Piscataway 08855-0789, USA.
Pharm Res. 1996 Apr;13(4):570-6. doi: 10.1023/a:1016098121784.
To develop, validate and apply a method for analyzing the intestinal perfusion data of highly permeable compounds using the Numerical Aqueous Resistance (NAR) theory and nonlinear regression (NAR-NLR) and to compare the results with the well-established Modified Boundary Layer (MBL) Analysis.
The NAR-NLR method was validated and the results were compared to the MBL analysis results using previously reported cephradine jejunal perfusion data. Using the Single Pass Intestinal Perfusion (SPIP) method, the concentration dependence of intestinal permeability was investigated for formycin B, proline, and thymidine, three compounds reported to be absorbed by carrier-mediated transport processes. The MBL and NAR-NLR analyses were then applied to the three sets of SPIP data.
The results demonstrate that the intrinsic MBL transport parameters were highly variable and, in one case, the analyses failed to give a statistically significant Michaelis constant. The MBL mean dimensionless wall permeabilities (Pw) were greater than the NAR-NLR Pw and were also highly variable. In all cases, the NAR-NLR variability was significantly lower than the MBL variability. The extreme variability in the MBL-calculated Pw is due to the sensitivity of Pw when the fraction of unabsorbed drug (Cm/Co) is low or, alternatively, when Pw approached the aqueous permeability, Paq.
The NAR-NLR method facilitates the analysis of intestinal perfusion data for highly permeable compounds such as those absorbed by carrier-mediated processes at concentrations below their Km. The method also allows for the use of a wider range of flow conditions than the MBL analysis resulting in more reliable and less variable estimates of intestinal transport parameters as well as intestinal wall permeabilities.
开发、验证并应用一种使用数值水阻力（NAR）理论和非线性回归（NAR-NLR）分析高渗透性化合物肠道灌注数据的方法，并将结果与成熟的修正边界层（MBL）分析进行比较。
使用先前报道的头孢拉定空肠灌注数据对NAR-NLR方法进行验证，并将结果与MBL分析结果进行比较。采用单通道肠道灌注（SPIP）方法，研究了甲酰溶肉瘤素、脯氨酸和胸苷这三种据报道通过载体介导转运过程吸收的化合物的肠道通透性浓度依赖性。然后将MBL和NAR-NLR分析应用于三组SPIP数据。
结果表明，内在的MBL转运参数变化很大，在一种情况下，分析未能得出具有统计学意义的米氏常数。MBL平均无量纲壁通透性（Pw）大于NAR-NLR的Pw，且变化也很大。在所有情况下，NAR-NLR的变异性均显著低于MBL的变异性。MBL计算的Pw的极大变异性是由于当未吸收药物的分数（Cm/Co）较低时，或者当Pw接近水通透性Paq时，Pw的敏感性所致。
NAR-NLR方法有助于分析高渗透性化合物的肠道灌注数据，例如那些在低于其Km的浓度下通过载体介导过程吸收的化合物。该方法还允许使用比MBL分析更广泛的流动条件，从而得出更可靠且变异性更小的肠道转运参数以及肠壁通透性估计值。
