residue—a derivatized lysine—at position 6; the diacetate salt endows the drug with excellent water solubility for preparation of an aqueous solution (0.5 mg/mL, pH 5.0) for parenteral administration (sc injection); the solution stability at pH 5.0 is such that ganirelix can be marketed as a sterile solution rather than a powder requiring reconstitution.
An overview of key structure-activity aspects for pep-tidic GnRH antagonists was provided within a pair of papers by Rivier et al.140,141 Although structural determinants of GnRH-R affinity and efficacy are now rather well understood, structural bases for alterations in duration of action remain much less so. Changes in peptide structure alter solubility characteristics, resistance to degrading enzymes, and plasma and tissue protein binding, all of which affect duration, and none of which can readily and reliably be predicted at present. The need for parenteral administration, especially for chronic applications, represents a liability among all of the marketed GnRH antagonists. Also, there is a modest but significant incidence of severe generalized hypersensitivity reactions; this problem with the Plenaxis product of abarelix acetate undoubtedly played a part in the decision by Praecis Pharmaceuticals to voluntarily discontinue sales in 2005, although components of the formulation other than the drug may have accounted for many of these reactions. (Defined structure-activity relationships for stimulation of histamine release from mast cells by peptides of this class have been reported, however—notably for variation at position 8.142) In any case, nonpeptide, orally bioavailable GnRH antagonists have been sought, and several compounds have advanced through phase II trials. Developments in this area were reviewed in detail by Betz et al. in mid-2008143; the interested reader is particularly encouraged to study this review, as the authors provide a highly instructive exposition of the structural determinants for agonist and antagonist actions at GnRH-Rs, and for receptor selectivity among GPCR ligands in general, based on the picture that emerged from a large collection of elegant reports. This review also offers up important lessons with regard to molecular pharmacodynamics—notably, the significances of ligand-binding kinetics with regard to efficacy and affinity variations, and to the origins of insurmountable versus surmountable antagonism. As yet, no crystal structures have become available for either unliganded or ligand-bound GnRH-R, but the aggregate work in this area makes abundantly clear the power of advanced protein modeling in conjunction with analysis of the effects of site-directed mutagenesis on the binding and action of ligands from various structural classes. Readily apparent also is the great worth of time- and resource-demanding efforts to discover/create such a variety of ligands, and conduct artfully designed and executed biological experiments with them.
The biological fates of the peptidic GnRH antagonists are partly characterized. Cetrorelix elimination occurs by renal and biliary routes.144-146 Following a 10-mg sc dose given to men and women, only unchanged cetrorelix was detected in urine, whereas chain-shortened fragments produced by the actions of peptidases were found in bile, with fragment (1-4) predominating and fragments (1-9), (1-7), and (1-6) present in significant quantities. Dose dependencies of elimination clearly show that these elimination pathways are saturable, and other than peptide hydrolysis, no other phase I biotransformations, nor any phase II transformations, occur significantly for cetrorelix. For ganirelix, cumulative elimination over 288 hours for a single 1-mg dose (iv) resulted in recovery of 75% of the dose in feces and 22% in urine.147,148 Any excretion in urine was reported to be complete within the first 24 hours, whereas fecal elimination did not approach completion until nearly 200-hour postdose. Elimination was found to be dose-proportional within the range of 0.125 to 0.5 mg. Fragment peptides (1-4 and 1-6) were the major components of fecal radioactivity, whereas no unchanged drug was detected in feces. Following depot injection, de-garelix undergoes peptide hydrolysis primarily in the hepato-biliary system, whereupon the majority of the cleavage products are excreted in bile.149
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