Info

Fibroids Miracle

Fibroids Alternative Treatments

Get Instant Access

Indications: A, palliative treatment of advanced prostate cancer; B, treatment of children with central precocious puberty; C, endometriosis; D, uterine leiomyomata (fibroids); E, palliative treatment of advanced breast cancer; F, ovarian carcinoma; G, paraphilia; H, pancreatic carcinoma; I, hypergonadism; J, growth hormone deficiency; K, in vitro fertilization assistance; M, assisted reproduction (LH surge suppression for timing control); N, to bring about presurgical endometrial thinning. "Sennello, L. T., Finley, R. A., Chu, S. Y., et al.: J. Pharm. Sci. 75(2):158-160, 1986. hEligard product information (8-Nov-2007 labeling). °Vantas product information (8-Nov-2004 labeling). dTrelstar product information (29-Jun-2001 labeling).

eZolodex product information (27-Jul-1998 labeling), or Facts and Comparisons' Web site, accessed April 2009. fSynarel product information (12-Apr-2006 labeling).

b.i.d., bis in die (twice a day); im, intramuscular; iv, intravenous; NA, not available; sc, subcutaneous.

Indications: A, palliative treatment of advanced prostate cancer; B, treatment of children with central precocious puberty; C, endometriosis; D, uterine leiomyomata (fibroids); E, palliative treatment of advanced breast cancer; F, ovarian carcinoma; G, paraphilia; H, pancreatic carcinoma; I, hypergonadism; J, growth hormone deficiency; K, in vitro fertilization assistance; M, assisted reproduction (LH surge suppression for timing control); N, to bring about presurgical endometrial thinning. "Sennello, L. T., Finley, R. A., Chu, S. Y., et al.: J. Pharm. Sci. 75(2):158-160, 1986. hEligard product information (8-Nov-2007 labeling). °Vantas product information (8-Nov-2004 labeling). dTrelstar product information (29-Jun-2001 labeling).

eZolodex product information (27-Jul-1998 labeling), or Facts and Comparisons' Web site, accessed April 2009. fSynarel product information (12-Apr-2006 labeling).

b.i.d., bis in die (twice a day); im, intramuscular; iv, intravenous; NA, not available; sc, subcutaneous.

buserelin pyro-Glu-His-Trp-Ser-Tyr-D-Ser(O-tBu) -

histrelin pyro-Glu-His-Trp-Ser-Tyr-D-His (IVx-Bz) -

goserelin pyro-Glu-His-Trp-Ser-Tyr-D-Ser(O-tBu) -

--Leu-Arg-Pro-Gly-NH2 --Leu-Arg-Pro-NHEt --Leu-Arg-Pro-NHEt --Leu-Arg-Pro-Gly-NH2 -Leu-Arg-Pro-NHEt --Leu-Arg-Pro-NHNHC(=0)NH2 --Leu-Arg-Pro-Gly-NH2 --Leu-Arg-Pro-NHEt

N terminus (pyro-Glu moiety)

N terminus (pyro-Glu moiety)

L-His2

D-Nal6 D-ß-(2-naphthylalanine) residue in nafarelin

L-His2

D-Nal6 D-ß-(2-naphthylalanine) residue in nafarelin

L-Pro9-Gly10-NH2 in GnRH, nafarelin, triptorelin

N terminus of of goserelin

D-Ser(O-f-Bu)6 residue in buserelin and goserelin

L-Pro9-NHEt terminus of leuprolide, buserelin, histrelin, and deslorelin

L-Pro9-Gly10-NH2 in GnRH, nafarelin, triptorelin

N terminus of of goserelin

L-Pro9-NHEt terminus of leuprolide, buserelin, histrelin, and deslorelin

D-(/Vr-benzyl)His6 residue in histrelin

L-Arg1 residue in triptorelin pamoate salt

Figure 20.32 • Primary sequences and selected substructures for endogenous human GnRH, and marketed GnRH agonists.

L-Arg1 residue in triptorelin pamoate salt

Nafarelin acetate is formulated for intranasal administration, the only nonparenteral formulation among the currently available GnRH agonists. Deslorelin acetate currently finds use only in veterinary medicine, such as for stimulating ovulation in mares (acute administration ^ flare effect) or helping to stabilize and maintain high-risk pregnancies in livestock, although clinical trials in humans for certain breast cancers, precocious puberty, and congenital adrenal hyperplasia are in progress or completed.

The marketed GnRH agonists are all close structural analogs of GnRH itself (Fig. 20.32). They are often called "superagonists" because they have increased potency and increased duration of action versus the endogenous agonist (GnRH), which is rapidly cleaved in the pituitary by endopeptidases (24.11 and 24.15)129 and has a very short half-life (2-4 minutes) in the systemic circulation. The reported agonist potencies relative to GnRH for some of these molecules are leuprolide (15-fold), buserelin (20fold), deslorelin (144-fold), and histrelin (210-fold).130 All of the marketed synthetic agonists incorporate, like GnRH, pyro-glutamic acid at the amino terminus, in which the N-terminal œ-amino group has undergone cyclocondensation with the y-carboxyl moiety of the same glutamate residue, forming a five-membered amide-containing ring—that is, a lactam moiety (more specifically, this constitutes a 5-oxopyrrolidine-2-carboxylic acid residue). The following four amino acids (positions 2-5) are also the same in all. Position 6 is the main point of structural variation among these GnRH-analog agonists; substitution is consistently with a d amino acid to confer peptidase resistance (see discussion that follows). Leuprolide (leuprore-lin), buserelin, histrelin, and deslorelin are nonapeptides rather than decapeptides: They lack the amidated C-termi-nal glycine, instead terminating at Pro9, which is amidated with ethylamine, thus forming an A-ethylprolinamide terminus. This terminal N-ethyl moiety can be viewed as an abbreviated stand-in for the terminal glycinamide moiety of GnRH. Goserelin terminates in an unusual (among medicinal substances) aminocarbonylhydrazide moiety, whereas nafarelin and triptorelin maintain the same structure at the C-terminus as GnRH. The goserelin N-terminus can be seen as a bioisosteric substitution: It is identical to that of the natural hormone except that an — NH— is substituted for the methylene ( — CH2 —) of the terminal glycine. All of the marketed agonists include the strongly basic Arg8 residue, so that, with no appreciably acidic groups elsewhere within the structure to provide an internal counterion, a salt form is obligatory; acetate is the counterion for most. Triptorelin is marketed in the United States as its pamoate salt (see Fig. 20.32), which provides for long duration of action by virtue of depot creation upon intramuscular injection.

The elimination processes and fates of these peptides are not fully characterized. For leuprolide, available information suggests that elimination is mostly via peptidase-catalyzed cleavage, and subsequent urinary excretion of peptide fragments.131 In healthy men, a pentapeptide is the prominent metabolite, and formation is relatively rapid, with levels of this metabolite peaking between 2- and 6-hour postdose. Following administration of the 3.75-mg depot suspension formulation, less than 5% of an administered dose was recovered as leuprolide and the pentapep-tide metabolite. Such extensive fragmentation does not occur with all of these analogous compounds; however, more than 40% of an iv bolus dose of triptorelin, for example, is recovered intact in urine.132 Although the overall elimination of histrelin has reportedly not been studied following insertion of 50-mg implants, biotransformation in human hepatic microsomes showed the presence of a single prominent metabolite resulting from N-deethylation of the C-terminal amide moiety.133 Peptidase-generated histrelin fragments are also likely, but the molecule is designed to be resistant to hydrolysis by endopeptidases 24.11 and 24.15. Nafarelin is extensively biotransformed. Following administration of (14C)nafarelin subcutaneously to men, at least six metabolites appeared in urine, collectively accounting for about half of the dose, with ~3% of the dose appearing in urine as unchanged nafarelin.

Hexapeptide Tyr5-Gly10(NH2) was the most prominent metabolite.134 The metabolites collectively persist in serum for much longer than the parent drug.

Gonadotropin-Releasing Hormone Antagonists

To some extent, the clinical uses of GnRH antagonists (Table 20.7) parallel those of the agonists discussed previously; however, antagonists do not, of course, generate the flare response.135 Instead, GnRH receptors in the go-nadotrope cells of the pituitary are blocked, so that pituitary output of FSH and LH is reduced or abolished. This response occurs rapidly, unlike the desensitization that develops over several weeks when GnRH agonists are used for gonadotropin suppression. Return to a pretreatment state also occurs relatively quickly, within 2 days after stopping lower doses of GnRH antagonists (except, of course, with depot injections).

The marketed GnRH antagonists (Fig. 20.33) were designed based on the GnRH structure,136 but contain many more alterations as compared with agonists, including more d amino acids, and numerous unnatural or derivatized side chains (the full structure of ganirelix, Fig. 20.34, provides an exemplary illustration). His2 was identified early on as important to receptor activation,137 and this residue is re

TABLE 20.7 GnRH Antagonists

Was this article helpful?

0 0
51 Tips for Dealing with Endometriosis

51 Tips for Dealing with Endometriosis

Do you have Endometriosis? Do you think you do, but aren’t sure? Are you having a hard time learning to cope? 51 Tips for Dealing with Endometriosis can help.

Get My Free Ebook


Post a comment