Physiologically based pharmacokinetic modeling of arterial - antecubital vein concentration difference.
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.
Levitt
David G
DG
Department of Physiology, University of Minnesota, Minneapolis, U.S.A. levit001@umn.edu
D000096:Acetone / Q000008:administration & dosage / Q000097:blood; D000328:Adult; D000465:Algorithms; D001158:Arteries / Q000502:physiology*; D001835:Body Weight / Q000502:physiology; D017666:Deuterium Oxide / Q000008:administration & dosage / Q000097:blood; D004334:Drug Administration Schedule; D004550:Elbow / Q000098:blood supply*; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage / Q000097:blood; D008297:Male; D008752:Methylene Chloride / Q000008:administration & dosage / Q000097:blood; D008954:Models, Biological; D010599:Pharmacokinetics; D012039:Regional Blood Flow / Q000502:physiology; D016284:Technetium Tc 99m Pentetate / Q000008:administration & dosage / Q000097:blood; D013874:Thiopental / Q000008:administration & dosage / Q000097:blood; D014050:Toluene / Q000008:administration & dosage / Q000097:blood; D014680:Veins / Q000502:physiology*
D000096:Acetone; D014050:Toluene; D000431:Ethanol; D008752:Methylene Chloride; D007649:Ketamine; D017666:Deuterium Oxide; D013874:Thiopental; D016284:Technetium Tc 99m Pentetate