TABLE 1

The kinetic parameters of loperamide metabolism and permeability in intestinal tissue from P-gp–competent or P-gp–deficient mice

The kinetic parameters of loperamide metabolism, Vmax and Km, were derived by measuring loperamide metabolites during its absorptive flux across intestinal tissue from P-gp–competent or P-gp–deficient mice (as described in the Materials and Methods section). The permeability values for loperamide (20 μM) are reported as Papp (–P450) and were determined in the presence of troleandomycin (100 μM) to inhibit oxidative metabolism of loperamide by Cyp3a. In the absence of troleandomycin, approximately 7 and 14% of loperamide (20 μM) was metabolized over the 90-minute period by the intestinal tissue from P-gp–competent and P-gp–deficient mice, respectively, during flux measurement (Fig. 2). Values are expressed as the mean ± S.D. of n = 3 mice with four intestinal tissues from each mouse. AQ for loperamide in mouse intestinal tissue is thus [0.5.5/(0.61 + 5.5)] = 0.9.

VmaxKmPapp(−P450)
pmol metabolite/min 
per cm2μMnm/sec
P-gp-competent31 ± 122 ± 4.8***0.61 ± 0.047***
P-gp deficient30 ± 3.24.5 ± 2.45.5 ± 1.1
  • P-gp, P-glycoprotein.

  • *** P < 0.001 significance between P-gp-competent and P-gp-deficient mice, as determined using a two-tailed Wilcoxon t test.