Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors

被引:150
作者
Proctor, NJ [1 ]
Tucker, GT [1 ]
Rostami-Hodjegan, A [1 ]
机构
[1] Univ Sheffield, Royal Hallamshire Hosp, Clin Sci Div S, Sheffield S10 2JF, S Yorkshire, England
关键词
D O I
10.1080/00498250310001646353
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1. Recombinantly expressed human cytochromes P450 (rhCYPs) have been underused for the prediction of human drug clearance (CL). 2. Differences in intrinsic activity (per unit CYP) between rhCYP and human liver enzymes complicate the issue and these discrepancies have not been investigated systematically. We define intersystem extrapolation factors (ISEFs) that allow the use of rhCYP data for the in vitro - in vivo extrapolation of human drug CL and the variance that is associated with interindividual variation of CYP abundance due to genetic and environmental effects. 3. A large database (n = 451) of metabolic stability data has been compiled and used to derive ISEFs for the most commonly used expression systems and CYP enzymes. 4. Statistical models were constructed for the ISEFs to determine major covariates in order to optimize experimental design to increase prediction accuracy. 5. Suggestions have been made for the conduct of future studies using rhCYP to predict human drug clearance.
引用
收藏
页码:151 / 178
页数:28
相关论文
共 133 条
[31]   INVITRO FORECASTING OF DRUGS WHICH MAY INTERFERE WITH THE BIOTRANSFORMATION OF MIDAZOLAM [J].
GASCON, MP ;
DAYER, P .
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1991, 41 (06) :573-578
[32]   CHARACTERIZATION OF DEXTROMETHORPHAN N-DEMETHYLATION BY HUMAN LIVER-MICROSOMES - CONTRIBUTION OF THE CYTOCHROME-P450 3A (CYP3A) SUBFAMILY [J].
GORSKI, JC ;
JONES, DR ;
WRIGHTON, SA ;
HALL, SD .
BIOCHEMICAL PHARMACOLOGY, 1994, 48 (01) :173-182
[33]   4-hydroxylation of debrisoquine by human CYP1A1 and its inhibition by quinidine and quinine [J].
Granvil, CP ;
Krausz, KW ;
Gelboin, HV ;
Idle, JR ;
Gonzalez, FJ .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2002, 301 (03) :1025-1032
[34]   Biotransformation of caffeine by cDNA expressed human cytochromes P-450 [J].
Ha, HR ;
Chen, J ;
Krahenbuhl, S ;
Follath, F .
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1996, 49 (04) :309-315
[35]   AN INVESTIGATION OF THE INTERACTION BETWEEN HALOFANTRINE, CYP2D6 AND CYP3A4 - STUDIES WITH HUMAN LIVER-MICROSOMES AND HETEROLOGOUS ENZYME EXPRESSION SYSTEMS [J].
HALLIDAY, RC ;
JONES, BC ;
SMITH, DA ;
KITTERINGHAM, NR ;
PARK, BK .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1995, 40 (04) :369-378
[36]   Cytochrome P4502B6 and 2C9 do not metabolize midazolam: kinetic analysis and inhibition study with monoclonal antibodies [J].
Hamaoka, N ;
Oda, Y ;
Hase, I ;
Asada, A .
BRITISH JOURNAL OF ANAESTHESIA, 2001, 86 (04) :540-544
[37]  
HARRIS JW, 1994, CANCER RES, V54, P4026
[38]   Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes [J].
Hemeryck, A ;
De Vriendt, C ;
Belpaire, FM .
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1999, 54 (12) :947-951
[39]  
Hickman D, 1998, DRUG METAB DISPOS, V26, P207
[40]   Prediction of hepatic clearance from microsomes, hepatocytes, and liver slices [J].
Houston, JB ;
Carlile, DJ .
DRUG METABOLISM REVIEWS, 1997, 29 (04) :891-922