Inter-individual variability in levels of human microsomal protein and hepatocellularity per gram of liver

被引:149
作者
Wilson, ZE [1 ]
Rostami-Hodjegan, A [1 ]
Burn, JL [1 ]
Tooley, A [1 ]
Boyle, J [1 ]
Ellis, SW [1 ]
Tucker, GT [1 ]
机构
[1] Univ Sheffield, Div Clin Sci S, Liver Grp, Sheffield, S Yorkshire, England
关键词
liver microsomes; prediction of metabolic clearance; cytochrome P450; in silico ADME; variability in metabolism;
D O I
10.1046/j.1365-2125.2003.01881.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Aims To determine levels of microsomal protein (MPPGL) and hepatocellularity (HPGL) per gram of human liver and their interindividual variability. Methods Triplicate liver samples were used to determine values of MPPGL (n = 20) and HPGL ( n = 7) after accounting for the fractional loss of microsomal protein or hepatocytes during processing. Repeated measurements from each liver sample allowed the estimation of true interindividual variability in MPPGL and HPGL using ANOVA. Results The value of MPPGL ranged from 26 to 54 mg g(-1) (mean(geo) = 33 mg g(-1)). The value of HPGL ranged from 65 to 185 x 10(6) cells g(-1) (mean(geo) = 107 x 10(6) cells g(-1)). Conclusions There is significant interindividual variability in MPPGL, which has implications for the accurate extrapolation of in vitro data on drug metabolism to predict in vivo metabolic clearance.
引用
收藏
页码:433 / 440
页数:8
相关论文
共 47 条
[1]  
Andersson TB, 2001, DRUG METAB DISPOS, V29, P712
[2]  
ARIAS IM, 1988, LIVER BIOL PATHOBIOL, P3
[3]  
BAARNHIELM C, 1986, ACTA PHARMACOL TOX, V59, P113
[4]   PREDICTION OF INTRINSIC CLEARANCE OF LOXTIDINE FROM KINETIC-STUDIES IN RAT, DOG AND HUMAN HEPATOCYTES [J].
BAYLISS, MK ;
BELL, JA ;
JENNER, WN ;
WILSON, K .
BIOCHEMICAL SOCIETY TRANSACTIONS, 1990, 18 (06) :1198-1199
[5]   THE CONCENTRATION OF CYTOCHROME-P-450 IN HUMAN HEPATOCYTE CULTURE [J].
BLAAUBOER, BJ ;
VANHOLSTEIJN, I ;
VANGRAFT, M ;
PAINE, AJ .
BIOCHEMICAL PHARMACOLOGY, 1985, 34 (13) :2405-2408
[6]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[7]   Microsomal prediction of in vivo clearance of CYP2C9 substrates in humans [J].
Carlile, DJ ;
Hakooz, N ;
Bayliss, MK ;
Houston, JB .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1999, 47 (06) :625-635
[8]   A commentary on the use of hepatocytes in drug metabolism studies during drug discovery and development [J].
Cross, DM ;
Bayliss, MK .
DRUG METABOLISM REVIEWS, 2000, 32 (02) :219-240
[9]  
EGGENS I, 1988, BRIT J EXP PATHOL, V69, P671
[10]   HUMAN ADULT HEPATOCYTES IN PRIMARY MONOLAYER-CULTURE - MAINTENANCE OF MIXED-FUNCTION OXIDASE AND CONJUGATION PATHWAYS OF DRUG-METABOLISM [J].
GRANT, MH ;
BURKE, MD ;
HAWKSWORTH, GM ;
DUTHIE, SJ ;
ENGESET, J ;
PETRIE, JC .
BIOCHEMICAL PHARMACOLOGY, 1987, 36 (14) :2311-2316