The long-term objective of this research program is to define the effects of various physiological perturbations on the pharmacokinetics of rapidly acting intravenous anesthetics to improve understanding of their dose- response relationships.
The specific aim of the proposed work is to describe, from the moment of injection, the simultaneous disposition of inert markers of the three physiological spaces important to drug distribution: indocyanine green (ICG), intravascular space; insulin, interstitial fluid space; and antipyrine, total body water. This multiple indicator dilution technique will allow assessment of changes in the processes responsible for drug distribution: mixing, flow, and diffusion. Traditional pharmacokinetic studies do not characterize the rise, fall, and subsequent oscillations in blood drug concentrations in the seconds after intravenous administration when anesthetic effects are maximal. The first study will further develop a model of initial drug distribution by describing the simultaneous disposition of ICG and antipyrine, from the moment of injection, in dogs anesthetized with halothane. A traditional, multicompartmental model for each physiological marker will for circulatory and tissue transit delays. This modification adds characterization of the blood indicator concentration versus time relationships seen in the seconds after intravenous administration to the traditional pharmacokinetic model. The effect of alterations in both cardiac output and the distribution of cardiac output on drug distribution by mixing, flow, and diffusion will be assessed in the second and third studies. The disposition of the three physiological markers will be described in dogs in two paradigms of altered cardiac output and distribution. One study will evaluate the effects of 1.0%, 1.5%, and 2.0% halothane while the other will examine the effects of moderate and severe hypovolemia and volume loading in the awake animal. Repeat measures Latin square experimental designs will be used to randomize in both of these studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM043776-01A1
Application #
3302815
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1991-01-01
Project End
1993-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Henthorn, T K; Krejcie, T C; Avram, M J (2008) Early drug distribution: a generally neglected aspect of pharmacokinetics of particular relevance to intravenously administered anesthetic agents. Clin Pharmacol Ther 84:18-22
Krejcie, T C; Avram, M J (1999) What determines anesthetic induction dose? It's the front-end kinetics, doctor! Anesth Analg 89:541-4
Krejcie, T C; Avram, M J; Gentry, W B et al. (1997) A recirculatory model of the pulmonary uptake and pharmacokinetics of lidocaine based on analysis of arterial and mixed venous data from dogs. J Pharmacokinet Biopharm 25:169-90
Krejcie, T C; Jacquez, J A; Avram, M J et al. (1996) Use of parallel Erlang density functions to analyze first-pass pulmonary uptake of multiple indicators in dogs. J Pharmacokinet Biopharm 24:569-88
Krejcie, T C; Henthorn, T K; Shanks, C A et al. (1994) A recirculatory pharmacokinetic model describing the circulatory mixing, tissue distribution and elimination of antipyrine in dogs. J Pharmacol Exp Ther 269:609-16
Gentry, W B; Krejcie, T C; Henthorn, T K et al. (1994) Effect of infusion rate on thiopental dose-response relationships. Assessment of a pharmacokinetic-pharmacodynamic model. Anesthesiology 81:316-24;discussion 25A
Henthorn, T K; Krejcie, T C; Shanks, C A et al. (1992) Time-dependent distribution volume and kinetics of the pharmacodynamic effector site. J Pharm Sci 81:1136-8
Henthorn, T K; Avram, M J; Krejcie, T C et al. (1992) Minimal compartmental model of circulatory mixing of indocyanine green. Am J Physiol 262:H903-10