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

抄録

  We previously established a method to predict the drug metabolism capacity of injured liver based on pharmacokinetic estimation of the amount of cytochrome P450 (CYP) in vivo (PKCYP test), by introducing the apparent liver-to-blood free concentration gradient in vivo (qg) as a parameter. Here we show that the amount of CYP3A2 in CCl₄-treated rats can be estimated appropriately by applying the PKCYP test using midazolam (MDZ) as a probe, assuming that the qg value in control rats does not change. We applied the results to predict the clearance of theophylline as a model drug with a physiologically based pharmacokinetic model.
   Male Sprague-Dawley rats were pretreated with CCl₄, and the amount of CYP (A-CYP_vivo) 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 (CL_tot) of theophylline in CCl₄-treated rats. The predicted CL_tot 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 CL_tot of theophylline in CCl₄-treated rats.