AJP - Endocrinology and Metabolism, Vol 258, Issue 3 E468-E475, Copyright © 1990 by American Physiological Society
Model of the distribution and metabolism of a GnRH superagonist in dogs
D. Lacoste, B. Candas, M. Normand and F. Labrie
Medical Research Council Group in Molecular Endocrinology, Laval University Medical Center, Quebec, Canada.
The plasma kinetics of [D-Trp6, des-Gly-NH2(10)]gonadotropin-releasing
hormone (GnRH) ethylamide was assessed in eight dogs over a period of 8 h
after rapid intravenous or subcutaneous injection. Each animal received
doses of 0.2, 2, and 20 micrograms/kg body wt iv and 1 and 10 micrograms/kg
body wt sc. A two-compartment structure, to which a source compartment was
added to represent the subcutaneous route, adequately fits the five
kinetics when the apparent volume of distribution follows a plasma
concentration-dependent sigmoid function. Despite the nonlinearity, the
apparent volume of distribution can be approximated by a constant value of
280 ml/kg body wt for the dynamics corresponding to the three lowest and
more physiological doses. The metabolic clearance rate is 4.63 ml.min-1.kg
body wt-1. The two exponential components that characterize the
two-compartment structure are equal to 0.0348 +/- 0.0053 and 0.00470 +/-
0.00060 min-1, respectively. The agonist injected subcutaneously diffuses
to plasma at a fractional rate of 0.0265 +/- 0.0029 min-1. Disposal occurs
at a maximal rate of 0.017 and 0.0055 min-1 of the amount of agonist
present in the central and peripheral compartments, respectively. The
highest fractional exchange rate between compartments reaches 0.01 min-1.
As simulated with the model, a continuous infusion of 4.63 ng.min-1.kg body
wt-1 leads to a steady state of 1 ng/ml plasma; 90% of that level is
reached 7 h after the onset of the subcutaneous input signal. The kinetics
of plasma [D-Trp6, des-Gly-NH2(10)]GnRH ethylamide is many times slower
than that of the native hormone and of the other GnRH agonists.
