title: Assessment of intestinal availability (FG) of substrate drugs of cytochrome p450s by analyzing changes in pharmacokinetic properties caused by drug-drug interactions.
abstract: 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: Departments of Pharmacology and Pharmacokinetics (A.H.) and Pharmacy (A.T., H.S.), University of Tokyo Hospital, Tokyo, Japan; Clinical Research Planning Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan (M.N.); and Laboratory for Safety Assessment and ADME, Asahi Kasei Pharma Corporation, Tokyo, Japan (S.K.) hisaka@chiba-u.jp.
authors: Akihiro
authors: A
authors: Hisaka
authors: Departments of Pharmacology and Pharmacokinetics (A.H.) and Pharmacy (A.T., H.S.), University of Tokyo Hospital, Tokyo, Japan; Clinical Research Planning Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan (M.N.); and Laboratory for Safety Assessment and ADME, Asahi Kasei Pharma Corporation, Tokyo, Japan (S.K.).
authors: Mikiko
authors: M
authors: Nakamura
authors: Departments of Pharmacology and Pharmacokinetics (A.H.) and Pharmacy (A.T., H.S.), University of Tokyo Hospital, Tokyo, Japan; Clinical Research Planning Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan (M.N.); and Laboratory for Safety Assessment and ADME, Asahi Kasei Pharma Corporation, Tokyo, Japan (S.K.).
authors: Ayako
authors: A
authors: Tsukihashi
authors: Departments of Pharmacology and Pharmacokinetics (A.H.) and Pharmacy (A.T., H.S.), University of Tokyo Hospital, Tokyo, Japan; Clinical Research Planning Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan (M.N.); and Laboratory for Safety Assessment and ADME, Asahi Kasei Pharma Corporation, Tokyo, Japan (S.K.).
authors: Saori
authors: S
authors: Koh
authors: Departments of Pharmacology and Pharmacokinetics (A.H.) and Pharmacy (A.T., H.S.), University of Tokyo Hospital, Tokyo, Japan; Clinical Research Planning Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan (M.N.); and Laboratory for Safety Assessment and ADME, Asahi Kasei Pharma Corporation, Tokyo, Japan (S.K.).
authors: Hiroshi
authors: H
authors: Suzuki
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D007408:Intestinal Absorption; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*
chemical_list: D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System