Abstract
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 FG from 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 FG values for 20 substrate drugs of CYP3A was 0.56 ± 0.29, whereas that for 8 substrate drugs of CYP2C9, CYP2C19, and CYP2D6 was 0.86 ± 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 FG separating from the absorption ratio (FA) although it requires approximation of FA. Since preciseness of approximation of FA does not greatly affect the evaluation of FG by the DDI method, we proposed a reasonable approximation method of FA for the evaluation of FG in the DDI method. The DDI method would be applicable to a broad range of situations in which various DDI data are utilizable.
Footnotes
- Received May 15, 2014.
- Accepted July 24, 2014.
↵1 Current affiliation: Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
This research was supported in part by a Grant-in-Aid for Scientific Research on Innovative Areas HD Physiology Project from the Japanese Ministry of Education, Culture, Sports, Science, and Technology [Grant 22136015].
↵This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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