Model of the distribution and metabolism of a GnRH superagonist in dogs.
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.
Lacoste
D
D
Medical Research Council Group in Molecular Endocrinology, Laval University Medical Center, Quebec, Canada.
Candas
B
B
Normand
M
M
Labrie
F
F
D000818:Animals; D001711:Biotransformation; D003429:Cross Reactions; D004285:Dogs; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D007106:Immune Sera; D007700:Kinetics; D008297:Male; D008433:Mathematics; D008954:Models, Biological; D011863:Radioimmunoassay; D014018:Tissue Distribution
D007106:Immune Sera; C062225:LHRH, Trp(6)-des-GlyNH2(10)-; D007987:Gonadotropin-Releasing Hormone