Assessment of intestinal availability (FG) of substrate drugs of cytochrome P450s by analyzing changes in pharmacokinetic properties caused by drug-drug interactions

摘要

In this study, we developed the drug-drug interaction (DDI) method as a new assessment technique of intestinal availability (FG, the fraction of drug transferred from the intestinal enterocytes into the liver, escaping from intestinal metabolism) based on the clearance theory. This method evaluates FGfrom changes caused by DDIs in the area under the blood concentration-time curve and in the elimination half-life of victim drugs. Application of the DDI method to data from the literature revealed that the mean and S.D. of FGvalues for 20 substrate drugs of CYP3A was 0.56 6 0.29, whereas that for 8 substrate drugs of CYP2C9, CYP2C19, and CYP2D6 was 0.86 6 0.11. These results were consistent with the fact that intestinal metabolism is mediated predominantly by CYP3A. The DDI method showed reasonable correlations with the conventional i.v./p.o. method and the grape fruit juice (GFJ) method (coefficients of determination of 0.41 and 0.81, respectively). The i.v./p.o. method was more susceptible to fluctuations in the hepatic blood flow rate compared with the DDI and GFJ methods. The DDI method evaluates FGseparating from the absorption ratio (FA) although it requires approximation of FA. Since preciseness of approximation of FA does not greatly affect the evaluation of FGby the DDI method, we proposed a reasonable approximation method of FAfor the evaluation of FGin the DDI method. The DDI method would be applicable to a broad range of situations in which various DDI data are utilizable.