TABLE 3.

Physicochemical evaluation and in vitro metabolism in human liver microsomes of the basic benzhydryl and nitrogenous heterocycle classes

^aThe relative loss of the parent compound and the formation of metabolic products following incubation in human liver microsomes were determined by liquid chromatography-mass spectrometry. The concentration of the test compound versus time was fitted to an exponential decay function to determine the first-order rate constant for substrate depletion. This rate constant was used to calculate the in vitro intrinsic clearance (CL_int) and the hepatic extraction ratio (E_H).

^bIn vitro metabolic stability groupings are as follows: very high, predicted hepatic extraction ratio (E_H) of >0.95; high, predicted E_H of 0.7 to 0.95; intermediate, predicted E_H of 0.3 to 0.7; low, predicted E_H of <0.3.

^cCalculated value.

^dThe two pK_a values shown for each form of compound 14 are for the ionization of their pyrimidine and quinazoline sites, respectively.

^eMeasured using a chromatographic elogD method (35).

^fMeasured using nephelometry (5).