Journal
DRUG METABOLISM AND DISPOSITION
Volume 42, Issue 10, Pages 1640-1645Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.114.059147
Keywords
-
Categories
Funding
- Japanese Ministry of Education, Culture, Sports, Science, and Technology [22136015]
- Grants-in-Aid for Scientific Research [22136015, 22136001] Funding Source: KAKEN
Ask authors/readers for more resources
In this study, we developed the drug-drug interaction (DDI) method as a new assessment technique of intestinal availability (F-G, the fraction of drug transferred from the intestinal enterocytes into the liver, escaping from intestinal metabolism) based on the clearance theory. This method evaluates F-G 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 F-G 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 F-G separating from the absorption ratio (F-A) although it requires approximation of F-A. Since preciseness of approximation of F-A does not greatly affect the evaluation of F-G by the DDI method, we proposed a reasonable approximation method of F-A for the evaluation of F-G in the DDI method. The DDI method would be applicable to a broad range of situations in which various DDI data are utilizable.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available