MODEL OF THE DISTRIBUTION AND METABOLISM OF THE GONADOTROPIN-RELEASING HORMONE (GNRH) AGONIST [D-TRP6,DES-GLY-NH210]GNRH ETHYLAMIDE IN MAN

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 Mc R is estimated at 1.18 mL/minA 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. © 1990 by The Endocrine Society.