Biomedical subjects

M V Evans

Publications and source records attributed to M V Evans.

3 recordsLinked to original sources

PubMed1994

Applications of sensitivity analysis to a physiologically based pharmacokinetic model for carbon tetrachloride in rats.

Physiologically based pharmacokinetic (PBPK) models developed from gas uptake experiments have been used to estimate metabolic parameters for 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 resulting estimates. Adult male F344 rats (165-205 g) were individually exposed to carbon tetrachloride (CCl4) in gas uptake systems. Three rats at each concentration were exposed for 6 hr to initial concentrations of 25, 100, 250, and 1000 ppm CCl4. Partition coefficient determinations were performed by the vial equilibration technique and used as model inputs. Computer optimizations with the means of each initial chamber concentration at each time point resulted in an estimate of Vmax of 0.11 mg/hr (Vmaxc = 0.37 mg/hr/kg) and Km of 1.3 mg/liter. To determine the effect of individual animal variation in Vmax, optimizations were also performed with the mean +/- SD, resulting in Vmax estimates of 0.09 and 0.12 mg/hr, respectively. Similar analysis resulted in Km estimates of 0.98 and 1.58 mg/liter. The results of the sensitivity analysis were concentration dependent for CCl4. These results show Vmax and Km to be most accurately detected at lower initial chamber concentrations. Results of the sensitivity analysis at the lowest concentration established the following model input hierarchy: blood to air partition > fat partition and fat volume fraction > slowly perfused partition, ventilation rate, cardiac output, fat blood flow percentage > liver blood flow percentage and slowly perfused blood flow percentage. Further sensitivity analysis determined Vmax and Km to be highly correlated when using gas uptake technology and point to the need to an independent estimate for either constant. In summary, the application of sensitivity analysis to PBPK modeling resulted in an increased understanding of factors governing the estimation of metabolic parameters.

Animals↗

PubMed1987

Time shift in ventilation-induced density fluctuation of arterial blood.

In an artificially ventilated dog, the varying tracheal pressure causes a density fluctuation in the blood sampled from the aorta. We cross-correlated the tracheal pressure with the density to determine the time shift or delay of the latter from the former waveform for a ventilation frequency in the range of 6-30 CPM. The delay time was found to be 29% of the mean transit time (MTT) of the pulmonary vasculature and independent of the ventilation frequency. A comparison of this percentage with the reported arterial-to-capillary-to-venous fractional volumes of the lung suggested that the delay time may be the MTT time for blood flowing through the venous network of the lung and the cross-correlation may serve as an in vivo means to partition the MTT of the pulmonary vasculature at its capillaries. These results and an analysis on the deformation of the viscoelastic, pulmonary capillaries indicated that the tracheal pressure, acting primarily through the viscous part of the viscoelasticity, deforms the capillaries to produce the density fluctuation in blood outflowing from the lung.

Animals↗

PubMed1985

A density method to quantify pulmonary microvascular hematocrit.

We perfused the left lower lobe of a dog with autologous blood having a hematocrit Ha. When the vascular pressure perfusing the lobe was elevated, we observed a transient increase in the density of venous blood. Converting the density increase to a rise in hematocrit, we could calculate a volume (Vr) of red blood cells (RBC) over their normal outflow that was released by the lobe as a result of the elevation. We measured the weight gain of the lobe to determine the increase in pulmonary vascular volume, V' - V. We found that the ratio, Vr/Ha/(V' - V), is 0.11 +/- 0.02. To determine the implication of this ratio, we divided the lobular vasculature into an arterial, microvascular, and venous compartment. Due to the Fahraeus effect, the tube hematocrit in the microvascular compartment (Hc) is lower than that of two macrovascular compartments, Ha. An analysis on the balance of RBC and plasma flows through the lobe identified the volume Vr as (Vc' - Vc) (Ha - Hc) with Vc' - Vc being the volumetric increase of the lobular microvascular compartment. Based on the reported volumetric fractional change of microvascular compartment, we estimated that the microvascular (tube) hematocrit in pulmonary capillaries is 80% (ranging from 78 to 82%) of the hematocrit perfusing the lobe. Since the additional RBC volume (Vr) being released from the lobe cannot be accounted for by transcapillary filtration or capillary recruitment, we conclude from this analysis that the measurement of the transient density change in pulmonary outflow can be used to quantify the microvascular hematocrit of the lung.

Animals↗