Mv. Evans et al., APPLICATIONS OF SENSITIVITY ANALYSIS TO A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR CARBON-TETRACHLORIDE IN RATS, Toxicology and applied pharmacology, 128(1), 1994, pp. 36-44
Physiologically based pharmacokinetic (PBPK) models developed from gas
uptake experiments have been used to estimate metabolic parameters fo
r volatile organic compounds. Due to the potential application of PBPK
models to estimate metabolic bioactivation constants in humans, it is
important to understand the complex nature of these models and the re
sulting estimates. Adult male F344 rats (165-205 g) were individually
exposed to carbon tetrachloride (CC1(4)) in gas uptake systems. Three
rats at each concentration were exposed for 6 hr to initial concentrat
ions of 25, 100, 250, and 1000 ppm CCl4. Partition coefficient determi
nations were performed by the vial equilibration technique and used as
model inputs. Computer optimizations with the means of each initial c
hamber concentration at each time point resulted in an estimate of V-m
ax of 0.11 mg/hr (V-maxc = 0.37 mg/hr/kg) and K-m of 1.3 mg/liter. To
determine the effect of individual animal variation in V-max optimizat
ions were also performed with the mean +/- SD, resulting in V-max esti
mates of 0.09 and 0.12 mg/hr, respectively. Similar analysis resulted
in K-m estimates of 0.98 and 1.58 mg/liter. The results of the sensiti
vity analysis were concentration dependent for CCl4. These results sho
w V-max and K-m to be most accurately detected at lower initial chambe
r concentrations. Results of the sensitivity analysis at the lowest co
ncentration established the following model input hierarchy: blood to
air partition > fat partition and fat volume fraction > slowly perfuse
d partition, ventilation rate, cardiac output, fat blood flow percenta
ge > liver blood flow percentage and slowly perfused blood flow percen
tage. Further sensitivity analysis determined V-max and K-m to be high
ly correlated when using gas uptake technology and point to the need t
o an independent estimate for either constant. In summary, the applica
tion of sensitivity analysis to PBPK modeling resulted in an increased
understanding of factors governing the estimation of metabolic parame
ters. (C) 1994 Academic Press, Inc.