Computer simulation of the effects of alterations in blood flows and body composition on thiopental pharmacokinetics in humans.
BACKGROUND
Understanding the influence of physiological variables on thiopental pharmacokinetics would enhance the scientific basis for the clinical usage of this anesthetic.


METHODS
A physiological pharmacokinetic model for thiopental previously developed in rats was scaled to humans by substituting human values for tissue blood flows, tissue masses, and elimination clearance in place of respective rat values. The model was validated with published serum concentration data from 64 subjects. The model was simulated after intravenous thiopental administration, 250 mg, over 1 min, to predict arterial plasma concentrations under conditions of different cardiac outputs, degrees of obesity, gender, or age.


RESULTS
The human pharmacokinetic model is characterized by a steady state volume of distribution of 2.2 l/kg, an elimination clearance of 0.22 l/min, and a terminal half-life of 9 h. Measured thiopental concentrations are predicted with an accuracy of 6 +/- 37% (SD). Greater peak arterial concentrations are predicted in subjects with a low versus a high cardiac output (3.1 and 9.4 l/min), and in subjects who are lean versus obese (56 and 135 kg). Acutely, obesity influences concentrations because it affects cardiac output. Prolonged changes are due to differences in fat mass. Changes with gender and age are relatively minor.


CONCLUSIONS
The physiological pharmacokinetic model developed in rats predicts thiopental pharmacokinetics in humans. Differences in basal cardiac output may explain much of the variability in early thiopental disposition between subjects.
Wada
D R
DR
Department of Anesthesia, Stanford University School of Medicine, California, USA. russellw@pharsight.com
Björkman
S
S
Ebling
W F
WF
Harashima
H
H
Harapat
S R
SR
Stanski
D R
DR
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics*; D000818:Animals; D001823:Body Composition; D002302:Cardiac Output; D003198:Computer Simulation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009765:Obesity / Q000378:metabolism; D051381:Rats; D012039:Regional Blood Flow; D012737:Sex Factors; D013874:Thiopental / Q000493:pharmacokinetics*
D018686:Anesthetics, Intravenous; D013874:Thiopental