Evaluation of animal models for intestinal first-pass metabolism of drug candidates to be metabolized by CYP3A enzymes via in vivo and in vitro oxidation of midazolam and triazolam

被引:4
作者
Kuze, J. [1 ]
Mutoh, T. [1 ]
Takenaka, T. [1 ]
Oda, N. [1 ]
Hanioka, N. [2 ]
Narimatsu, S. [2 ]
机构
[1] Taiho Pharmaceut Co, Tsukuba Res Ctr, Ibaraki, Japan
[2] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Lab Hlth Chem, Okayama 7008530, Japan
关键词
CYP3A; human; intestinal first-pass metabolism; mechanism-based inactivation; midazolam; mouse; rat; substrate inhibition; triazolam; RNA EXPRESSION PROFILES; FREE GRAPEFRUIT JUICE; CYTOCHROME-P450; 3A4; ACTIVE-SITE; P-GLYCOPROTEIN; MESSENGER-RNAS; BIOTRANSFORMATION; BINDING; LIVER; RAT;
D O I
10.3109/00498254.2012.751517
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1. To search an appropriate evaluation methodology for the intestinal first-pass metabolism of new drug candidates, grapefruit juice (GFJ)- and vehicle (tap water)-pretreated mice or rats were orally administered midazolam (MDZ) or triazolam (TRZ), and blood levels of the parent compounds and their metabolites were measured by liquid chromatography/MS/MS. A significant effect of GFJ to elevate the blood levels was observed only for TRZ in mice. 2. In vitro experiments using mouse, rat and human intestinal and hepatic microsomal fractions demonstrated that GFJ suppressed the intestinal microsomal oxidation of MDZ and especially TRZ. Substrate inhibition by MDZ caused reduction in 1'-hydroxylation but not 4-hydroxylation in both intestinal and hepatic microsomal fractions. The kinetic profiles of MDZ oxidation and the substrate inhibition in mouse intestinal and hepatic microsomal fractions were very similar to those in human microsomes but were different from those in rat microsomes. Furthermore, MDZ caused mechanism-based inactivation of cytochrome P450 3A-dependent TRZ 1'-hydroxylation in mouse, rat and human intestinal microsomes with similar potencies. 3. These results are useful information in the analysis of data obtained in mouse and rat for the evaluation of first-pass effects of drug candidates to be metabolized by CYP3A enzymes.
引用
收藏
页码:598 / 606
页数:9
相关论文
共 36 条
[1]   Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice [J].
Bailey, D. G. ;
Dresser, G. K. ;
Leake, B. F. ;
Kim, R. B. .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 2007, 81 (04) :495-502
[2]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[3]   Sex-related differences in the clearance of cytochrome P450 3A4 substrates may be caused by P-glycoprotein [J].
Cummins, CL ;
Wu, CY ;
Benet, LZ .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 2002, 72 (05) :474-489
[4]   Human extrahepatic cytochromes P450: Function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts [J].
Ding, XX ;
Kaminsky, LS .
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2003, 43 :149-173
[5]  
Domanski TL, 2000, J PHARMACOL EXP THER, V293, P585
[6]  
Edwards DJ, 1996, DRUG METAB DISPOS, V24, P1287
[7]   Importance of P-glycoprotein for drug disposition in humans [J].
Fromm, MF .
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, 2003, 33 :6-9
[8]   Specific CYP3A4 inhibitors in grapefruit juice: furocoumarin dimers as components of drug interaction [J].
Fukuda, K ;
Ohta, T ;
Oshima, Y ;
Ohashi, N ;
Yoshikawa, M ;
Yamazoe, Y .
PHARMACOGENETICS, 1997, 7 (05) :391-396
[9]   Intestinal and hepatic metabolic activity of five cytochrome p450 enzymes: Impact on prediction of first-pass metabolism [J].
Galetin, Aleksandra ;
Houston, J. Brian .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2006, 318 (03) :1220-1229
[10]   Membrane transporters in drug development [J].
Giacomini, Kathleen M. ;
Huang, Shiew-Mei ;
Tweedie, Donald J. ;
Benet, Leslie Z. ;
Brouwer, Kim L. R. ;
Chu, Xiaoyan ;
Dahlin, Amber ;
Evers, Raymond ;
Fischer, Volker ;
Hillgren, Kathleen M. ;
Hoffmaster, Keith A. ;
Ishikawa, Toshihisa ;
Keppler, Dietrich ;
Kim, Richard B. ;
Lee, Caroline A. ;
Niemi, Mikko ;
Polli, Joseph W. ;
Sugiyama, Yuicchi ;
Swaan, Peter W. ;
Ware, Joseph A. ;
Wright, Stephen H. ;
Yee, Sook Wah ;
Zamek-Gliszczynski, Maciej J. ;
Zhang, Lei .
NATURE REVIEWS DRUG DISCOVERY, 2010, 9 (03) :215-236