AJP - Regulatory, Integrative and Comparative Physiology, Vol 253, Issue 2 352-R360, Copyright © 1987 by American Physiological Society
Allopurinol kinetics in humans as a means to assess liver function: comparison of different models
G. van Waeg, T. Groth, F. Niklasson and C. H. de Verdier
To describe the mechanisms involved in allopurinol kinetics after
intravenous injection in humans, a number of alternative computer-based
biodynamic models were designed. Distribution processes were described with
two-compartment as well as with three-compartment kinetics for both
allopurinol and its metabolite oxipurinol. These two major physiological
alternatives were combined with biochemical models assuming either
competitive or tight-binding-complex inhibition kinetics. The four
resulting basic models were evaluated (and successively improved) using
sets of plasma allopurinol and oxipurinol concentration curves, measured
after intravenous injection in healthy subjects and in patients with
different degrees of liver function. A three-compartment model with
tight-binding-complex inhibition was selected and used to analyze the 35
loading tests performed. One of the parameters estimated in this way, the
fractional rate constant for transport of allopurinol from the central
compartment to the metabolically active (liver) compartment (kA31), turned
out to be a powerful discriminative parameter between a group of healthy
subjects, a group of patients with slightly to moderately reduced overall
liver function, and a group with severely reduced overall liver function
[kA31(min-1) = 0.136 +/- 0.042 (mean +/- SD, n = 13), 0.072 +/- 0.024 (n =
13), and 0.025 +/- 0.015 (n = 8), respectively].
