Prediction of Theophylline Clearance in CCl4-treated Rats Using in vivo CYP1A2 and CYP3A2 Contents Assessed with the PKCYP Test

Male Sprague-Dawley rats were pretreated with CCl4, and the amount of CYP (A-CYPvivo) was quantified by Western blotting. The qg value of MDZ was determined in control rats and used to estimate the amounts of CYP3A2 in CCl4-treated rats; the result agreed well with the observed values. The qg value of CYP3A2 estimated with MDZ as a probe was used together with our previously reported value for CYP1A2 (theophylline metabolism in the liver is known to be almost entirely mediated by CYP3A2 and CYP1A2) to predict the total body clearance (CLtot) of theophylline in CCl4-treated rats. The predicted CLtot was about one-third of the observed value, which was considered acceptable. The time-course of theophylline concentration in serum simulated with a physiologically-based pharmacokinetic model agreed well with the observed values. Thus, the PKCYP test using MDZ as a probe can be used to predict the amount of CYP3A2 and the CLtot of theophylline in CCl4-treated rats.