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Covariation of human microsomal protein per gram of liver with age: absence of influence of operator and sample storage may justify interlaboratory data pooling.

Authors
Barter-ZE; Chowdry-JE; Harlow-JR; Snawder-JE; Lipscomb-JC; Rostami-Hodjegan-A
Source
Drug Metab Dispos 2008 Dec; 36(12):2405-2409
NIOSHTIC No.
20034836
Abstract
Scaling of metabolic clearance values from liver microsomal data or recombinantly expressed cytochrome P450 enzymes to predict human hepatic clearance requires knowledge of the amount of microsomal protein per gram of liver (MPPGL). Identification of physiological covariates of MPPGL requires analysis of values from large diverse populations, which necessitates pooling of data from numerous sources. To ensure compatibility between results obtained within and between studies, the impact of interoperator differences and sample storage on values of MPPGL was investigated. With use of triplicate samples from one liver (HL86), no statistically significant difference was detected between values of MPPGL prepared from samples stored at -80 degrees C ( 23.5 +/- 1.2 mg g(-1)) and those determined using fresh tissue ( 21.9 +/- 0.3 mg g(-1)). Although there was a significant difference in the yield of microsomal protein obtained from another liver sample ( HL43) by three different operators ( 17 +/- 1, 19 +/- 2, and 24 +/- 1 mg g(-1); p = 0.004, analysis of variance), no difference was observed in the estimated MPPGL after application of appropriate correction factors for each operator ( 28 +/- 1, 30 +/- 5, and 31 +/- 4 mg g(-1)). The result provided justification for pooling reported values of MPPGL for use in covariate analysis. Investigation of the relationship between age and MPPGL provided preliminary evidence that MPPGL values increase from birth to a maximum of 40 mg g(-1) [ 95% confidence interval for the geometric mean ( 95% CI mean(geo)): 37-43 mg g(-1)] at approximately 28 years followed by a gradual decrease in older age ( mean of 29 mg g(-1) at 65 years; 95% CI meangeo: 27-32 mg g(-1)). Accordingly, appropriate age-adjusted scaling factors should be used in extrapolating in vitro clearance values to clinical studies.
Keywords
Cell-biology; Cell-function; Cellular-reactions; Biochemistry; Biological-effects; Liver-cells; Liver-function; Liver-microsomal-enzymes; Liver-microsomal-metabolism; Liver-microsomes; Hepatic-microsomal-enzymes; Age-factors; Statistical-analysis
Contact
Dr. Zoe Barter, Floor M, The Royal Hallamshire Hospital, Sheffield S10 2JF, UK
CODEN
DMDSAI
Publication Date
20081201
Document Type
Journal Article
Email Address
z.barter@sheffield.ac.uk
Fiscal Year
2009
NTIS Accession No.
NTIS Price
Issue of Publication
12
ISSN
0090-9556
NIOSH Division
DART
Priority Area
Agriculture, Forestry and Fishing; Manufacturing; Construction
Source Name
Drug Metabolism and Disposition
State
OH
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