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Model of the Distribution and Metabolism of the Gonadotropin-Releasing Hormone (GnRH) Agonist [D-Trp⁶,Des-Gly-NH₂¹⁰]GnRH Ethylamide in Man

Department of Physiology, Faculty of Medicine, Laval University (B.C., M.N.) Quebec, Canada GlK 7P4
Laboratory of Molecular Endocrinology, CHUL Research Center (D.L., F.L.) Quebec, Canada G1V4G2

Address requests for reprints to: Dr. Fernand Labrie, Director, Medical Research Council Group in Molecular Endocrinology, 2705 Laurier Boulevard, Ste-Foy, Quebec, Canada GlK 7P4.

The kinetics of plasma immunoreactive [D-Trp⁶,Des-Gly-NH₂¹⁰]GnRH ethylamide, a potent GnRH agonist, was assessed in nine normal adult men over a period of 24 h after a rapid sc injection of 1 or 10 µg peptide/kg BW. The specific RIA of the GnRH agonist is characterized by a minimum detectable dose of 5.0 ± 0.5 pg peptide, while the midrange effective dose is 73 ± 8 pg. The within- and between-assay coefficients of variation range from 2–7% and from 10–15%, respectively. When the volume of the central compartment is set proportional to the logarithm of the plasma concentration of the GnRH agonist, the time courses of both doses are statistically well represented by a two-compartment model to which a source compartment is added to represent the sc route of administration. The sc diffusion to plasma is 5 times faster than any other fractional transport rate of the model (5%/min). Disposal occurs at a maximum rate of 0.55%/min from the central compartment, which includes plasma, and 0.25%/min from the peripheral compartment. As simulated with the model, 90% of the steady state is reached 13 h and 45 min after the onset of a sc continuous infusion. A molecule spends, on the average, from 6 h to 9 h and 45 min in the whole organism; 30-50% of this period is accounted for by residence in the central compartment. The volume of the central compartment reaches 208 mL/kg BW, and the MCR is estimated at 1.18 mL/min·kg BW for a steady state of 1 ng/mL plasma. The plasma dynamics of [D-Trp⁶,Des-Gly-NH₂¹⁰]GnRH ethylamide in men are at least 10 times slower than those reported for the natural GnRH, thus indicating the relevance of its clinical use in suppressive therapy of LH secretion.

Received September 12, 1989.