We investigated these systems with the V min -based pK BHX workflow described above, and found that the pyrimidine ring in A.17 was predicted to show significantly increased hydrogen-bond basicity. The basicity of the pyrimidine increased by 0.6 pK BHX units, thus offsetting any potential gains in lipophilicity. In contrast, pyrrolotriazine A.20 showed dramatic improvements in permeability and efflux ratio, which can be attributed to the computed 0.7 pK BHX -unit decrease in the hydrogen-bond basicity of the aromatic nitrogen.