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Physiologically based pharmacokinetic modeling of arterial - antecubital vein concentration difference.

Levitt DG - BMC Clin Pharmacol (2004)

Bottom Line: In most cases, experimental measurements are only available for a peripheral vein (usually antecubital) whose concentration may differ significantly from both arterial and central vein concentration.A significantly different set of "arm" parameters was required to describe the data for D2O, acetone, methylene chloride and toluene - probably because the "arm" is in a different physiological state.Also, the antecubital vein concentration can be used to estimate the arterial concentration for an arbitrary input for solutes for which no arterial concentration data is available.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, University of Minnesota, Minneapolis, U.S.A. levit001@umn.edu

ABSTRACT

Background: Modeling of pharmacokinetic parameters and pharmacodynamic actions requires knowledge of the arterial blood concentration. In most cases, experimental measurements are only available for a peripheral vein (usually antecubital) whose concentration may differ significantly from both arterial and central vein concentration.

Methods: A physiologically based pharmacokinetic (PBPK) model for the tissues drained by the antecubital vein (referred to as "arm") is developed. It is assumed that the "arm" is composed of tissues with identical properties (partition coefficient, blood flow/gm) as the whole body tissues plus a new "tissue" representing skin arteriovenous shunts. The antecubital vein concentration depends on the following parameters: the fraction of "arm" blood flow contributed by muscle, skin, adipose, connective tissue and arteriovenous shunts, and the flow per gram of the arteriovenous shunt. The value of these parameters was investigated using simultaneous experimental measurements of arterial and antecubital concentrations for eight solutes: ethanol, thiopental, 99Tcm-diethylene triamine pentaacetate (DTPA), ketamine, D2O, acetone, methylene chloride and toluene. A new procedure is described that can be used to determine the arterial concentration for an arbitrary solute by deconvolution of the antecubital concentration. These procedures are implemented in PKQuest, a general PBPK program that is freely distributed http://www.pkquest.com.

Results: One set of "standard arm" parameters provides an adequate description of the arterial/antecubital vein concentration for ethanol, DTPA, thiopental and ketamine. A significantly different set of "arm" parameters was required to describe the data for D2O, acetone, methylene chloride and toluene - probably because the "arm" is in a different physiological state.

Conclusions: Using the set of "standard arm" parameters, the antecubital vein concentration can be used to determine the whole body PBPK model parameters for an arbitrary solute without any additional adjustable parameters. Also, the antecubital vein concentration can be used to estimate the arterial concentration for an arbitrary input for solutes for which no arterial concentration data is available.

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Comparison of toluene PBPK model arterial (red line) and antecubital vein (blue line) concentrations with the experimental data (squares) of Carlsson et. al. [17] (top panel). The bottom panel compares the model antecubital vein/arterial concentration ratio (black line) versus the experimental values (squares). Using a fractional contribution of muscle to antecubital vein blood of 0.5.
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Figure 11: Comparison of toluene PBPK model arterial (red line) and antecubital vein (blue line) concentrations with the experimental data (squares) of Carlsson et. al. [17] (top panel). The bottom panel compares the model antecubital vein/arterial concentration ratio (black line) versus the experimental values (squares). Using a fractional contribution of muscle to antecubital vein blood of 0.5.

Mentions: A value of frmuscle of 0.4 to 0.5 is also required to describe to describe the antecubital vein concentration data for the volatile solutes. Figures 9, 10, 11 shows the results of the PBPK model analysis using a value of frmuscle of 0.5 (and frshunt of 0.075) for acetone, methylene chloride and toluene. This large muscle (and negligible shunt) contribution to antecubital vein blood is consistent with the previous PBPK modeling of Johanson and Naslund [36] of the arterial and antecubital vein concentrations for volatile solutes. They were able to describe the experimental data assuming that the antecubital vein blood was supplied entirely by muscle and skin. The fit at long times in fig. 9 is poor for the acetone data. Wigaeus et. al. [15] commented in the original paper that there was something anomalous about the acetone data at long times because the venous concentration remained lower than the arterial concentration for the entire 2 hour washout period. This is very difficult to explain and would be consistent with a direct loss of acetone from the tissues of the hand and arm.


Physiologically based pharmacokinetic modeling of arterial - antecubital vein concentration difference.

Levitt DG - BMC Clin Pharmacol (2004)

Comparison of toluene PBPK model arterial (red line) and antecubital vein (blue line) concentrations with the experimental data (squares) of Carlsson et. al. [17] (top panel). The bottom panel compares the model antecubital vein/arterial concentration ratio (black line) versus the experimental values (squares). Using a fractional contribution of muscle to antecubital vein blood of 0.5.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC375538&req=5

Figure 11: Comparison of toluene PBPK model arterial (red line) and antecubital vein (blue line) concentrations with the experimental data (squares) of Carlsson et. al. [17] (top panel). The bottom panel compares the model antecubital vein/arterial concentration ratio (black line) versus the experimental values (squares). Using a fractional contribution of muscle to antecubital vein blood of 0.5.
Mentions: A value of frmuscle of 0.4 to 0.5 is also required to describe to describe the antecubital vein concentration data for the volatile solutes. Figures 9, 10, 11 shows the results of the PBPK model analysis using a value of frmuscle of 0.5 (and frshunt of 0.075) for acetone, methylene chloride and toluene. This large muscle (and negligible shunt) contribution to antecubital vein blood is consistent with the previous PBPK modeling of Johanson and Naslund [36] of the arterial and antecubital vein concentrations for volatile solutes. They were able to describe the experimental data assuming that the antecubital vein blood was supplied entirely by muscle and skin. The fit at long times in fig. 9 is poor for the acetone data. Wigaeus et. al. [15] commented in the original paper that there was something anomalous about the acetone data at long times because the venous concentration remained lower than the arterial concentration for the entire 2 hour washout period. This is very difficult to explain and would be consistent with a direct loss of acetone from the tissues of the hand and arm.

Bottom Line: In most cases, experimental measurements are only available for a peripheral vein (usually antecubital) whose concentration may differ significantly from both arterial and central vein concentration.A significantly different set of "arm" parameters was required to describe the data for D2O, acetone, methylene chloride and toluene - probably because the "arm" is in a different physiological state.Also, the antecubital vein concentration can be used to estimate the arterial concentration for an arbitrary input for solutes for which no arterial concentration data is available.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, University of Minnesota, Minneapolis, U.S.A. levit001@umn.edu

ABSTRACT

Background: Modeling of pharmacokinetic parameters and pharmacodynamic actions requires knowledge of the arterial blood concentration. In most cases, experimental measurements are only available for a peripheral vein (usually antecubital) whose concentration may differ significantly from both arterial and central vein concentration.

Methods: A physiologically based pharmacokinetic (PBPK) model for the tissues drained by the antecubital vein (referred to as "arm") is developed. It is assumed that the "arm" is composed of tissues with identical properties (partition coefficient, blood flow/gm) as the whole body tissues plus a new "tissue" representing skin arteriovenous shunts. The antecubital vein concentration depends on the following parameters: the fraction of "arm" blood flow contributed by muscle, skin, adipose, connective tissue and arteriovenous shunts, and the flow per gram of the arteriovenous shunt. The value of these parameters was investigated using simultaneous experimental measurements of arterial and antecubital concentrations for eight solutes: ethanol, thiopental, 99Tcm-diethylene triamine pentaacetate (DTPA), ketamine, D2O, acetone, methylene chloride and toluene. A new procedure is described that can be used to determine the arterial concentration for an arbitrary solute by deconvolution of the antecubital concentration. These procedures are implemented in PKQuest, a general PBPK program that is freely distributed http://www.pkquest.com.

Results: One set of "standard arm" parameters provides an adequate description of the arterial/antecubital vein concentration for ethanol, DTPA, thiopental and ketamine. A significantly different set of "arm" parameters was required to describe the data for D2O, acetone, methylene chloride and toluene - probably because the "arm" is in a different physiological state.

Conclusions: Using the set of "standard arm" parameters, the antecubital vein concentration can be used to determine the whole body PBPK model parameters for an arbitrary solute without any additional adjustable parameters. Also, the antecubital vein concentration can be used to estimate the arterial concentration for an arbitrary input for solutes for which no arterial concentration data is available.

Show MeSH
Related in: MedlinePlus