Covariation of Human Microsomal Protein Per Gram of Liver with Age: Absence of Influence of Operator and Sample Storage May Justify Interlaboratory Data Pooling

Covariation of Human Microsomal Protein Per Gram of Liver with Age: Absence of Influence of Operator and Sample Storage May Justify Interlaboratory Data Pooling

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 analys...

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Bibliographic Details
Published in:Drug metabolism and disposition Vol. 36; no. 12; pp. 2405 - 2409
Main Authors: BARTER, Z. E, CHOWDRY, J. E, HARLOW, J. R, SNAWDER, J. E, LIPSCOMB, J. C, ROSTAMI-HODJEGAN, A
Format: Journal Article
Language:English
Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-12-2008
Subjects:
Adolescent
Adult
Age Factors
Aged
Aged, 80 and over
Analytical, structural and metabolic biochemistry
Biological and medical sciences
Child
Child, Preschool
Clinical Chemistry Tests - statistics & numerical data
Cryopreservation
Cytochrome P-450 Enzyme System - analysis
Female
Fetus - chemistry
Fundamental and applied biological sciences. Psychology
General aspects, investigation methods
Humans
Linear Models
Male
Microsomes, Liver - chemistry
Middle Aged
Models, Statistical
Observer Variation
Proteins
Proteins - analysis
Specimen Handling - statistics & numerical data
Young Adult
Human
Digestive system
Liver
Variability
Conservation
Laboratory measurement
Clearance
Microsome
Protein
Scaling function
Storage
Laboratory test
Pharmacokinetics
Age
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Summary: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°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 mean geo : 27–32 mg g -1 ). Accordingly, appropriate age-adjusted scaling factors should be used in extrapolating in vitro clearance values to clinical studies.
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ISSN:0090-9556
1521-009X
DOI:10.1124/dmd.108.021311