Differences In Clearance Values Research Articles

Influence of Sampling Site and Fluid Flow on the Accuracy of Total Body Clearance Calculation

Studies have showed that by assuming arteriovenous drug concentrations are homogenous after intravenous injection, the determination of total body clearance based on venous drug concentrations is often inaccurate. This study considers the use of a fluidic pharmacokinetic profile generator where 28 different profile types were generated corresponding to a physiological model with varying sampling sites, administration locations, and fluid flow rates. Clearance was calculated using established equations, commercial software, and recently proposed models. The results show large differences in clearance values calculated with published equations and commercial software relative to the actual value of clearance. Alterations in sampling site, administration location, and fluid flow rates each influence the extent of calculation errors. The data show that a significant drug concentration gradient exists within the central circulatory system. The results show that the best way to address this issue would be to inject the drug at a peripheral location to allow for sufficient mixing and then sample from a large vein. Extrapolating for missing data can also lead to large errors in clearance calculation; this can be addressed by collecting more samples early after IV bolus administration or by collecting data during steady state conditions for an IV infusion.

Endogenous creatinine clearance measurement of glomerular filtration rate in dogs

Summary Renal clearance procedures were performed on adult mixed-breed dogs with a wide range of renal function. Endogenous creatinine clearance was computed after analyzing plasma and urine for creatinine by use of 2 methods, PAP and kinetic Jaffe. For 20-minute clearance procedures, [14C]inulin clearance was measured simultaneously with endogenous creatinine clearance. For 111 twenty-minute clearance procedures performed on 24 dogs, [14C]inulin clearance was highly correlated with creatinine clearance for both methods of creatinine analysis (R2 = 0.979 for [14C]inulin-PAP; R2 = 0.943 for [14C]inulin-Jaffe). The absolute values for PAP and [14C]inulin clearance were nearly the same (PAP-to-[14C]inulin clearance ratio = 1.03 ± 0.08), but those for Jaffe clearance were substantially less than those for [14C]inulin clearance (Jaffe-to-[14C]inulin clearance ratio = 0.88 ± 0.10). The Jaffe-to-[14C]inulin clearance ratio was inversely correlated with degree of renal function (R2= 0.464), whereas the PAP-to-[14C]inulin clearance ratio was not correlated with degree of renal function (R2 = 0.060). Thus, Jaffe-determined creatinine clearance varied, in relation to [14C]inulin clearance, depending on degree of renal function. In 4 clinically normal dogs, 20-minute and 24-hour sample collections analyzed by use of the PAP method gave clearance values significantly greater, for both periods, than did Jaffe analyses. The PAP-determined creatinine clearance values were less than, but not significantly different from 20-minute exogenous creatinine clearance values determined 10 days after 24-hour collections. For 20-minute and 24-hour collections, the difference in clearance values between the PAP and Jaffe methods was attributable mostly to lower plasma creatinine values for the PAP method (mean ± SEM, plasma PAP-to-Jaffe ratio = 0.798 ± 0.053). However, urine creatinine values also were less by use of the PAP method (urine PAP-to-Jaffe ratio = 0.943 ± 0.103). We conclude that PAP-determined creatinine clearance reliably measured glomerular filtration rate during 20-minute collections, and probably during 24-hour collections as well. By contrast, Jaffe-determined creatinine clearance underestimated glomerular filtration rate by a variable amount.

Effects of surgical stress and insulin on cardiovascular function and norepinephrine kinetics

In resting supine subjects the whole-body clearance of norepinephrine (NE) based on arterial and venous sampling averaged 1.4 and 2.5 liters/min, respectively (P less than 0.02). The difference in clearance values was due to a peripheral uptake of NE averaging 45%. The calculation of plasma NE clearance based on venous sampling results in values that are too high. The plasma appearance rate of NE increased considerably after surgery, whereas the arterial blood pressure remained unchanged. This suggests that the sensitivity to NE is reduced postsurgery. Insulin has certain acute effects on cardiovascular function and plasma NE kinetics that are unrelated to the counterregulatory response to decrements in plasma glucose concentration. Insulin may both induce antagonism to the action of NE and increase the release of NE from sympathetic nerves. Intravenous insulin decreases the plasma volume and increases the hematocrit by an adrenergic mechanism. Plasma NE increases in normal subjects after an oral glucose load. This response may be of importance because in sympathectomized patients both oral glucose and insulin administration decreases the arterial blood pressure. During an oral glucose load insulin-dependent diabetics show abnormalities in the regulation of cardiovascular function and sympathetic nervous activity that may be related to the lack of rise in endogenous insulin in these patients. These results suggest that insulin may be of importance for the normal function of the cardiovascular system.

Whole body clearance of norepinephrine. The significance of arterial sampling and of surgical stress.

The whole body clearance of norepinephrine (NE) was measured in seven patients pre- and postoperatively. L[(3)H]NE was infused intravenously for 90 min and steady-state concentrations of L[(3)H]NE were measured at 75 and 90 min in both arterial and peripheral venous blood. Preoperatively, in the resting supine position, the clearance values based on arterial and venous sampling averaged 1.4 and 2.5 liter/min, respectively (P < 0.02). The difference in clearance values was due to a peripheral uptake of NE averaging 45%. The mean plasma NE increased from 1.70 nmol/liter preoperatively to 5.20 nmol/liter postoperatively (P < 0.02). The plasma appearance rate of NE averaged 2.4 nmol/min before surgery and it increased to 9.5 nmol/min postoperatively (P < 0.02). The plasma clearance of NE averaged 1.4 and 1.6 liter/min pre- and postoperatively, respectively (not significantly different). Our study demonstrates that the calculation of plasma NE clearance based on venous sampling results in values that are too high. Furthermore, such values may be influenced by individual variations in the peripheral uptake of NE, since we found no correlation between clearance values based on venous and arterial sampling. The increase in plasma NE postoperatively was due to an increase in the plasma appearance rate of NE because the clearance rate did not change.